Antiparasitic isoxazoline compounds, long-acting injectable formulations comprising them, methods and uses thereof

ABSTRACT

This invention relates to long-acting injectable compositions for combating parasites in animals, comprising at least one isoxazoline active agent, a liquid PEG and/or a neutral oil, optionally a co-solvent, and optionally a pharmaceutically acceptable additive or excipient. This invention also provides new isoxazoline active agents with long-lasting efficacy against ectoparasites. The invention also provides for improved methods for eradicating, controlling, and preventing parasite infections and infestations in an animal comprising administering the novel isoxazoline compounds and long-acting injectable compositions of the invention to the animal in need thereof.

FIELD OF THE INVENTION

The present invention provides pesticidal and antiparasitic isoxazolinecompounds, and long-acting injectable compositions comprising at leastone isoxazoline active agent, a liquid polyethylene glycol (PEG) and,optionally, a co-solvent. The invention also provides for the use ofthese compounds and compositions against pests and parasites (includingectoparasites (e.g., fleas or ticks) and/or endoparasites), and methodsfor controlling pests and preventing or treating parasitic infectionsand infestations in animals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 15/441,297, filed Feb. 24, 2016, which claims the benefit ofpriority to U.S. Provisional Application Nos. 62/299,333, filed Feb. 24,2016, and 62/379,348, filed Aug. 25, 2016, all of which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

Animals such as mammals and birds are often susceptible to parasiteinfestations/infections. These parasites may be ectoparasites, such asfleas, ticks and parasitic flies, and endoparasites such as nematodesand other worms. Domesticated animals, such as cats and dogs, are ofteninfested with one or more of the following ectoparasites:

-   -   fleas (e.g. Ctenocephalides spp., such as Ctenocephalides felis        and the like);    -   ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp.,        Amblyomma spp., and the like);    -   mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., and        the like);    -   lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus        spp. and the like);    -   mosquitoes (Aedes spp., Culex spp., Anopheles spp. and the        like); and    -   flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia        spp., Cochliomyia spp. and the like).

Fleas are a particular problem because not only do they adversely affectthe health of the animal or human, but they also cause a great deal ofpsychological stress. Moreover, fleas may also transmit pathogenicagents to animals and humans, such as tapeworm (Dipylidium caninum).

Similarly, ticks are also harmful to the physical and psychologicalhealth of the animal or human. However, the most serious problemassociated with ticks is that they are vectors of pathogenic agents inboth humans and animals. Major diseases which may be transmitted byticks include borreliosis (Lyme disease caused by Borrelia burgdorferi),babesiosis (or piroplasmosis caused by Babesia spp.) and rickettsioses(e.g. Rocky Mountain spotted fever). Ticks also release toxins whichcause inflammation or paralysis in the host. Occasionally, these toxinsare fatal to the host.

Likewise, farm animals are also susceptible to parasite infestations.For example, cattle and other bovines are affected by a large number ofparasites. A parasite which is prevalent among cattle in some regionsare ticks of the genus Rhipicephalus, especially those of the speciesmicroplus (cattle tick), decoloratus and annulatus. Ticks such asRhipicephalus microplus (formerly Boophilus microplus) are difficult tocontrol because they lay eggs in the pasture where farm animals graze.This species of ticks is considered a one-host tick and spends immatureand adult stages on one animal before the female engorges and falls offthe host to lay eggs in the environment. The life cycle of the tick isapproximately three to four weeks. In addition to cattle, Rhipicephalusmicroplus may infest buffalo, horses, donkeys, goats, sheep, deer, pigs,and dogs. A heavy tick burden on animals can decrease production anddamage hides as well as transmit diseases such as babesiosis (“cattlefever”) and anaplasmosis.

Animals and humans also suffer from endoparasitic infections including,for example, helminthiasis which is caused by of parasitic wormscategorized as cestodes (tapeworm), nematodes (roundworm) and trematodes(flatworm or flukes). These parasites adversely affect the nutrition ofthe animal and cause severe economic losses in pigs, sheep, horses, andcattle as well as affecting companion animals and poultry. Otherparasites which occur in the gastrointestinal tract of animals andhumans include those from the genus Ancylostoma, Necator, Ascaris,Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris,Enterobius and parasites which are found in the blood or other tissuesand organs such as filarial worms and the extra intestinal stages ofStrongyloides, Toxocara and Trichinella.

Recently, isoxazole and isoxazoline-containing compounds have beendemonstrated to be effective against parasites that harm animals. Forexample, U.S. Pat. No. 7,964,204 (to DuPont, incorporated by referenceherein in its entirety) discloses isoxazoline compounds according toformula (I) below, which are active against ectoparasites and/orendoparasites.

In addition, published patent application nos. US 2010/0254960 A1, WO2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 A1, U.S. Pat. No.7,951,828 & U.S. Pat. No. 7,662,972, US 2010/0137372 A1, US 2010/0179194A2, US 2011/0086886 A2, US 2011/0059988 A1, US 2010/0179195 A1 and WO2007/075459 A2 and U.S. Pat. Nos. 7,951,828 and 7,662,972 describevarious other parasiticidal isoxazoline compounds. Other publishedpatent applications that describe various other parasiticidalisoxazoline compounds and compositions comprising the same include WO2007/079162 A1, WO 2008/154528 A1, WO 2009/002809 A2, WO 2011/149749 A1,WO 2014/439475 A1, U.S. Pat. No. 8,466,115, WO 2012/120399, WO2014/039484, WO 2014/189837, (Zoetis) and WO2012 120135A1 (Novartis). WO2012/089623 describes topical localized isoxazoline compositionscomprising glycofurol. WO 2013/039948 A1 provides for topical veterinarycompositions comprising at least one isoxazoline active agent and WO2013/119442 A1 provides for oral veterinary compositions such as a softchew which comprising at least one isoxazoline active agent.

In additional to topical and oral dosage forms, it is sometimes possibleto formulate active agents as long-acting compositions, depending upon,for example, the physiochemical properties of the individual activeagent; these properties include, for example, solubility,bioavailability, etc. For example, U.S. Pat. Nos. 6,733,767 and8,362,086 provide for long acting injectable compositions comprising abioactive substance, such as, for example, an avermectin or a milbemycinand a biological acceptable polymer.

Notwithstanding the highly active isoxazoline active agents andcompositions comprising isoxazoline active agents alone or incombination with other active agents described in the documents above,there is a need for more effective isoxazoline compounds and veterinarycompositions and methods with improved efficacy, bioavailability, andspectrum of coverage to protect animals against endoparasites and/orectoparasites. More specifically, there is a need to develop along-acting injectable composition comprising an isoxazoline compound,which has good bioavailability and exhibits a reduced irritation at theinjection site while still being effective against parasites (e.g.,fleas and ticks) for a long duration (e.g., from three (3) to six (6)months.

INCORPORATION BY REFERENCE

Any foregoing applications, and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides for novel andinventive long-acting injectable compositions for the treatment orprevention of parasite infections or infestations in an animalcomprising an antiparasitic effective amount of at least one isoxazolinecompound, a liquid PEG and/or a pharmaceutically acceptable neutral oil,optionally, a co-solvent and optionally a pharmaceutically acceptableadditive or excipient.

In accordance with the first aspect of the present invention, it hasbeen discovered that the inventive long-acting compositions generallyshow desirable bioavailability and duration of efficacy, while causingminimal irritation at the injection site. The compositions also providedesirable safety profiles toward the warm-blooded and bird animalrecipients. In addition, it has been discovered that a singleadministration of such compositions generally provides potent activityagainst one or more parasites (e.g., ectoparasites), while also tendingto provide fast onset of activity, long duration of activity, and/ordesirable safety profiles.

The invention encompasses uses or veterinary uses of the isoxazolinecompounds and compositions described herein for the treatment orprevention of parasitic infections and infestations in or on animals(either wild or domesticated), including livestock and companion animalssuch as cats, dogs, horses, chickens, sheep, goats, pigs, turkeys andcattle, with the aim of ridding these hosts of parasites commonlyencountered by such animals.

In addition, the compounds of formula (Id) described herein are usefulfor protecting crops, plants, plant propagation material, or materialcontaining wood or derived from wood, from harmful pests.

The invention also provides methods for the treatment or prevention ofparasitic infections and infestations in animals, comprisingadministering an effective amount of long-acting injectable compositionscomprising an antiparasitic effective amount of at least one isoxazolinecompound together with at least one liquid PEG and/or a pharmaceuticallyacceptable neutral oil and optionally a co-solvent, a pharmaceuticallyacceptable additive and/or excipient, wherein the composition does notcontain a pharmaceutically acceptable biodegradable polymer as definedherein. Surprisingly, it has been found that the inventiveisoxazoline-containing compositions described herein exhibit superiorbroad spectrum efficacy against harmful parasites (e.g. ectoparasitessuch as fleas and ticks) more rapidly, and over a long duration comparedto other injectable compositions containing isoxazoline active agentsknown in the art while exhibiting minimal irritation at the injectionsite.

This invention also provides for the use of an isoxazoline in thepreparation of a long-acting injectable composition for the treatment orprevention of an animal against parasites.

In one embodiment, the invention provides for long-acting injectablecompositions comprising antiparasitic effective amounts of at least oneisoxazoline of formula (I) below, in combination and a pharmaceuticallyor veterinary acceptable liquid carrier, where variables A¹, A², A³, A⁴,A⁵, A⁶, B¹, B², B³, R¹, R², R⁴, R⁵, W and n are defined herein.

In another embodiment, the invention provides long-acting injectablecompositions comprising an isoxazoline compound of formula (Ic):

or a pharmaceutically acceptable salt thereof; wherein X¹, X² and X³ areeach independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl. Long actingcompositions comprising a compound of formula (Ic) wherein X¹ is chloro,X² is fluoro and X³ is CF₃ have been shown to have surprisinglylong-lasting and excellent efficacy against Rhipicephalus microplus witha quick onset and a very long duration of time.

In another embodiment, the long-acting injectable compositions andmethods comprise4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamideas the active agent.

In other embodiments, the long-acting injectable compositions mayfurther comprise one or more additional active agents that aresystemically active. Systemically-acting active agents may include, butare not limited to, isoxazoline active agents of different structure, asystemically-acting neonicotinoid active agent, a systemically-acting1-N-arylpyrazole active agent, macrocyclic lactones such as avermectinand milbemycin compounds, a cyclic depsipeptide such as emodepside orPF1022A or analogs thereof, benzimidazoles, imidazothiazoles, atetrahydropyrimidine active agent, an organophosphate active agent,levamisole, a paraherquamide active agent and/or a marcfortine activeagent, praziquantel, closantel, clorsulon, morantel, pyrantel, aspinosyn or spinosoid active agent, an amino acetonitrile active agent,an aryloazol-2-yl cyanoethyl active agent, a systemically-acting insectgrowth regulator. In one embodiment, the long-acting injectablecompositions comprise at least one macrocyclic lactone active agent,including, but not limited to, avermectins or milbemycins. In someembodiments, the avermectin or milbemycin active agent is eprinomectin,ivermectin, selamectin, milbemectin, milbemycin D, milbemycin oxime, ormoxidectin.

In other embodiments, the compositions and methods comprise at least oneof thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole,albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel,praziquantel, closantel, clorsulon, an amino acetonitrile active agent,or an aryloazol-2-yl cyanoethylamino active agent.

In a second aspect, the invention provides novel and inventivepesticidal and parasiticidal isoxazoline compounds of formula (Id)shown:

wherein X¹ is bromo, chloro, iodo or fluoro; and X² is chloro, fluoro orCF₃;

Y is a group Y-1, Y-2, Y-3, Y-4 where Z is N or CH, Y-5 or Y-6

and Q is OH, —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃, —C(O)NHCH₂CH₂SCH₃or (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃.

The compounds of formula (Id) are highly active against arthropod pestsand parasites and useful for protecting animals, including livestock andcompanion animals such as cats, dogs, horses, chickens, sheep, goats,pigs, turkeys and cattle, from parasites that infest or infect suchanimals. The invention also provides pesticidal isoxazoline compounds offormula (Id) for protecting crops, plants, plant propagation material,or material containing wood or derived from wood, from harmful pests.

It is an object of the invention to not encompass within the inventionany previously known product, process of making the product, or methodof using the product such that the Applicants reserve the right andhereby disclose a disclaimer of any previously known product, process,or method. It is further noted that the invention does not intend toencompass within the scope of the invention any product, process, ormaking of the product or method of using the product, which does notmeet the written description and enablement requirements of the USPTO(35 U.S.C. § 112, first paragraph) or the EPO (Article 83 of the EPC),such that Applicants reserve the right and hereby disclose a disclaimerof any previously described product, process of making the product, ormethod of using the product.

These and other embodiments are disclosed or are obvious from andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION

Long-Acting Injectable Compositions

In a first aspect, the present invention provides for novel andinventive long-acting injectable compositions for the treatment orprevention of parasitic infections or infestations in an animalcomprising an antiparasitic effective amount of at least one isoxazolinecompound, a liquid PEG and/or a pharmaceutically acceptable neutral oil,and optionally a co-solvent, a pharmaceutically acceptable additiveand/or excipient, wherein no other pharmaceutically acceptable polymers,as defined herein are present.

Also provided are methods and uses for the treatment and/or prophylaxisof parasitic infections and infestations in or on animals, comprisingadministering to an animal in need thereof a long-acting compositioncomprising an antiparasitic effective amount of at least one isoxazolinecompound, a liquid PEG and/or a pharmaceutically acceptable neutral oil,and optionally a co-solvent, a pharmaceutically acceptable additiveand/or excipient.

In another embodiment, the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising anantiparasitic effective amount of at least one isoxazoline compound andan effective amount of at least one additional active agent, a PEGand/or a pharmaceutically acceptable neutral oil and, optionally, aco-solvent, a pharmaceutically acceptable additive and/or excipient.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prophylaxis of parasiticinfections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, which is:

-   -   i) an isoxazoline compound of formula (I):

wherein:

A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from the groupconsisting of CR³ and N, provided that at most 3 of A¹, A², A³, A⁴, A⁵and A⁶ are N;

B¹, B² and B³ are independently selected from the group consisting ofCR² and N;

W is O or S;

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, each optionally substitutedwith one or more substituents independently selected from R⁶;

each R² is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂;

each R³ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN or —NO₂;

R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl;

R⁵ is H, OR¹⁰, NR¹¹R¹² or Q¹; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁷; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂ alkoxy; each R⁶ is independently halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, —CNor —NO₂;

each R⁷ is independently halogen; C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₂-C₇alkylcarbonyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉dialkylaminocarbonyl, C₂-C₇ haloalkylcarbonyl, C₂-C₇ haloalkoxycarbonyl,C₂-C₇ haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl, hydroxy,—NH₂, —CN or —NO₂; or Q²;

each R⁸ is independently halogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, C₂-C₄ alkoxycarbonyl, —CN or —NO₂;

each R⁹ is independently halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN, —NO₂, phenyl or pyridinyl;

R¹⁰ is H; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one of more halogen;

R¹¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl;

R¹² is H; Q³; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one or more substituents independentlyselected from R⁷; or

R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂ alkoxy;

Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-or 10-membered fused bicyclic ring system optionally containing one tothree heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, eachring or ring system optionally substituted with one or more substituentsindependently selected from R⁸;

each Q² is independently a phenyl ring or a 5- or 6-memberedheterocyclic ring, each ring optionally substituted with one or moresubstituents independently selected from R⁹;

Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ringoptionally substituted with one or more substituents independentlyselected from R⁹; and

n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

ii) an isoxazoline compound of formula (II):

wherein:

R₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachwhich is unsubstituted or substituted with one or more of halogen,hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—,R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

X is aryl or heteroaryl, which may be unsubstituted or substituted byone or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

A₁ is oxygen; and

A₂ is oxygen, NR₂ or CR₇R₈;

G is G-1 or G-2;

B₁, B₂, B₃, B₄ and B₅ are independently N or C—R₉; Y is hydrogen,halogen, —CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, orheterocyclyl or heteroaryl each of which is unsubstituted or substitutedwith one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino,alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—,R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or—NO₂; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11,Y-12 or Y-13;

R₂, R₃ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, R₁₀S(O)—, R₁₀S(O)₂—, R₁₀C(O)—,R₁₀C(S)—, R₁₀R₁₁NC(O)—, R₁₀R₁₁NC(S)— R₁₀OC(O)—;

R₄, R₅ and R₆ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;

R₇ and R₈ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynylor haloalkynyl;

R₉ is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each which is unsubstituted or substituted with one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

R₁₀, R₁₁, R₁₂ and R₁₃ are each independently hydrogen, alkyl, haloalkyl,thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,haloalkenyl, alkynyl or haloalkynyl; or

R₁₀ together with R₁₁ form ═O, ═S or ═NR₂; or

R₁₂ together with R₁₃ form ═O, ═S or ═NR₂;

W is O, S or NR₂,

n is 1-4; and

m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

-   -   iii) an isoxazoline compound of formula (III)

or a pharmaceutically acceptable salt thereof; and/or

-   -   iv) an isoxazoline compound of formula (IV)

or a pharmaceutically acceptable salt thereof; and/or

-   -   v) an isoxazoline compound of formula (V):

wherein R¹, R² and R³ are independently H, Cl, F or CF₃;

Y is the diradical group

and

T is a C₁-C₆-alkyl group which is unsubstituted or substituted byhalogen, cyano, nitro, amino, hydroxyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-alkylthio, carboxy, carbamoyl or C₂-C₆-alkanoylgroup which may be unsubstituted or substituted in the alkyl portion byhalogen or a pharmaceutical acceptable salt thereof; and/or

-   -   vi) an isoxazoline compound of formula (VI):

wherein Y is hydrogen, fluoro, chloro or bromo;

-   -   R¹ is phenyl substituted with 2-4 substituents selected from        halogen, methyl, difluoromethyl, trifluoromethyl, methoxy,        trifluoromethoxy or trifluoroethoxy;    -   R² is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;    -   R^(3a) and R^(3b) are independently selected from hydrogen,        methyl, ethyl or fluoromethyl; or R^(3a) and R^(3b) together        combine with the carbon to which they are attached to form a        cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically        acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prophylaxis of parasiticinfections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, which is:

-   -   i) an isoxazoline compound of formula (I) as described above, or        a pharmaceutically acceptable salt thereof; and/or    -   ii) an isoxazoline compound of formula (II) as described above,        or a pharmaceutically acceptable salt thereof; and/or    -   iii) an isoxazoline compound of formula (III) as described        above, or a pharmaceutically acceptable salt thereof; and/or    -   iv) an isoxazoline compound of formula (IV) as described above,        or a pharmaceutically acceptable salt thereof; and/or    -   v) an isoxazoline compound of formula (V) as described above, or        a pharmaceutically acceptable salt thereof; and/or    -   vi) an isoxazoline compound of formula (VI) as described above,        or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prophylaxis of parasiticinfections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, which is:

-   -   i) an isoxazoline compound of formula (I) as described above, or        a pharmaceutically acceptable salt thereof; and/or    -   ii) an isoxazoline compound of formula (II) as described above,        or a pharmaceutically acceptable salt thereof; and/or    -   iii) an isoxazoline compound of formula (III) as described        above, or a pharmaceutically acceptable salt thereof; and/or    -   iv) an isoxazoline compound of formula (IV) as described above,        or a pharmaceutically acceptable salt thereof; and/or    -   v) an isoxazoline compound of formula (V) as described above, or        a pharmaceutically acceptable salt thereof; and/or    -   vi) an isoxazoline compound of formula (VI) as described above,        or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (I) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (I) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prophylaxis of parasiticinfections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazoline activeagent of formula (I) described above, or a pharmaceutically acceptablesalt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ia):

-   -   or a pharmaceutically acceptable salt thereof

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, a surfactant, and optionally at least one otherpharmaceutically acceptable additive, excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol,benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is ethanol,isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ia) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ib):

or a pharmaceutically acceptable salt thereof

wherein

R² independently is halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl

R⁴ is H or C₁-C₆ alkyl;

R⁵ is C₁-C₄ alkyl optionally substituted with one or more R⁷; and R⁷ isC₂-C₇ alkylcarbonyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl,C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylcarbonyl, C₂-C₇haloalkoxycarbonyl, C₂-C₇ haloalkylaminocarbonyl, C₃-C₉dihaloalkylaminocarbonyl (e.g., —CH₂C(O)NHCH₂CF₃); and

n is 0, 1 or 2;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol,benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is ethanol,isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ib) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (II) as described above, or a pharmaceuticallyacceptable salt thereof,

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (II) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (II) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formulae II-1.001 to II-1.025 or II-2.00-II-2.018:

Compounds II-1.001 to II-1.025

Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵ R¹⁶ 1.001 3,5-Cl₂ C—H C—H C—HC—H N H CH₂C(O)NHCH₂CF₃ 1.002 3,5-Cl₂ C—H C—H C—H C—H N H CH₂CF₃ 1.0033,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂CO₂CH₃ 1.004 3,5-(CF₃)₂ C—H C—H C—HC—H N CH₃ CH₂CO₂H 1.005 3,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂C(O)NHCH₂CF₃1.006 3,5-(CF₃)₂ C—H C—H C—H C—H N H CH₂C(O)NHCH₂CF₃ 1.007 3,5-(CF₃)₂C—H C—H C—H C—H N H CH₂CH₂SCH₃ 1.008 3,5-(CF₃)₂ C—H C—H C—H C—H C—H HCH₂C(O)NHCH₂CF₃ 1.009 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃ 1.0103,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂CF₃ 1.011 3,5-Cl₂ C—H C—H C—H C—HC—H H CH₂C(O)NHCH₂CF₃ 1.012 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂CF₃ 1.0133,5-Cl₂ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃ 1.014 3-Cl, 5-CF₃ C—H C—H C—HC—H C—H H CH₂C(O)NHCH₂CF₃ 1.015 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CF₃1.016 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃ 1.017 3,5-Cl₂ C—H C—HC—Me C—H C—Me H CH₂C(O)NHCH₂CF₃ 1.018 3,5-Cl₂ C—H C—H C—Me C—H C—Me HCH₂CF₃ 1.019 3,5-Cl₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃ 1.020 3,5-(CF₃)₂C—H C—H C—Me C—H C—Me H CH₂C(O)NHCH₂CF₃ 1.021 3,5-(CF₃)₂ C—H C—H C—MeC—H C—Me H CH₂CF₃ 1.022 3,5-(CF₃)₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃1.023 3-Cl, 5-CF₃ C—H C—H C—Me C—H C—Me H CH₂C(O)NHCH₂CF₃ 1.024 3-Cl,5-CF₃ C—H C—H C—Me C—H C—Me H CH₂CF₃ 1.025 3-Cl, 5-CF₃ C—H C—H C—Me C—HC—Me H CH₂CH₂SCH₃

Compounds II-2.001 to II-2.018

Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵ R¹⁶ 2.001 3,5-Cl₂ C—H C—H N C—HC—H H CH₂C(O)NHCH₂CF₃ 2.002 3,5-Cl₂ C—H C—H N C—H C—H H CH₂CF₃ 2.0033,5-Cl₂ C—H C—H N C—H C—H H CH₂CH₂SCH₃ 2.004 3,5-(CF₃)₂ C—H C—H N C—HC—H H CH₂C(O)NHCH₂CF₃ 2.005 3,5-(CF₃)₂ C—H C—H N C—H C—H H CH₂CF₃ 2.0063,5-(CF₃)₂ C—H C—H N C—H C—H H CH₂CH₂SCH₃ 2.007 3-Cl, 5-CF₃ C—H C—H NC—H C—H H CH₂C(O)NHCH₂CF₃ 2.008 3-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂CF₃2.009 3-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂CH₂SCH₃ 2.010 3,5-Cl₂ C—H C—HC—H C—H C—H H CH₂C(O)NHCH₂CF₃ 2.011 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂CF₃2.012 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃ 2.013 3,5-(CF₃)₂ C—H C—HC—H C—H C—H H CH₂C(O)NHCH₂CF₃ 2.014 3,5-(CF₃)₂ C—H C—H C—H C—H C—H HCH₂CF₃ 2.015 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃ 2.016 3-Cl,5-CF₃ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 2.017 3-Cl, 5-CF₃ C—H C—HC—H C—H C—H H CH₂CF₃ 2.018 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formulae II-1.001 to II-1.025 or II-2.00-II-2.018 asdescribed above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formulae II-1.001 to II-1.025 or II-2.00-II-2.018 asdescribed above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (III)

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is aC₁-C₆alcohol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

iv) an antiparasitic effective amount of an isoxazoline compound offormula (IV) as described above, or a pharmaceutically acceptable saltthereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol,benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is ethanol,isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (IV) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (V) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (V) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (V) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising

a) an antiparasitic effective amount of an isoxazoline compound offormula (Va):

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol,benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is ethanol,isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Va) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising

a) an antiparasitic effective amount of at least one compound of formula(VI) as described above, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VI) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VI) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one compound of formula(VIa):

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In still another embodiment, the present invention provides for along-acting injectable composition for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations in or on animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol,benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VIa) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the long-acting injectable compositions ofpresent invention comprise an antiparasitic effective amount of at leastone isoxazoline of formula (Ib), which has the formula:

or a pharmaceutically acceptable salt thereof

wherein

R² independently is halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl

R⁴ is H or C₁-C₆ alkyl;

R⁵ is C₁-C₄ alkyl optionally substituted with one or more R⁷; and R⁷ isC₂-C₇ alkylcarbonyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl,C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylcarbonyl, C₂-C₇haloalkoxycarbonyl, C₂-C₇ haloalkylaminocarbonyl, C₃-C₉dihaloalkylaminocarbonyl (e.g., —CH₂C(O)NHCH₂CF₃); and

n is 0, 1 or 2.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic):

or a pharmaceutically acceptable salt thereof

wherein

X¹, X² and X³ are each independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In one embodiment, the long-acting injectable compositions of theinvention comprise a compound of formula (Ic) wherein X¹ and X³ areindependently halogen and X² is hydrogen.

In another embodiment, the long-acting injectable compositions of theinvention comprise a compound of formula (Ic), wherein X¹, X² and X³ areeach independently halogen.

In another embodiment of the invention, the long-acting injectablecompositions comprise a compound of formula (Ic), wherein X¹ and X³ areeach independently halogen and X² is C₁-C₃haloalkyl.

In still another embodiment, the invention provides a long-actinginjectable composition comprising a compound of formula (Ic), wherein X¹and X² are independently halogen and X³ is C₁-C₃haloalkyl.

In another embodiment, the invention provides a long-acting injectablecomposition comprising a compound of formula (Ic), wherein X¹ and X² areindependently halogen and X³ is CF₃.

In another embodiment, the invention provides a long-acting injectablecomposition comprising a compound of formula (Ic), wherein X¹ and X³ arechloro and X² is hydrogen.

In yet another embodiment, the invention provides a long-actinginjectable composition comprising a compound of formula (Ic), wherein X¹is chloro, X² is fluoro and X³ is CF₃.

In another embodiment, the invention provides a long-acting injectablecomposition comprising a compound of formula (Ic), wherein X¹ and X³ arechloro and X² is fluoro.

In another embodiment, the long-acting injectable compositions ofpresent invention comprise an antiparasitic effective amount of4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide(Compound of formula Ia).

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic):

or a pharmaceutically acceptable salt thereof

wherein

X¹ and X³ are each independently halogen or C₁-C₃haloalkyl; and

X² is halogen or hydrogen;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) shown above, or a pharmaceutically acceptable salt thereof,wherein

X¹ and X³ are each independently halogen or C₁-C₃haloalkyl; and

X² is halogen or hydrogen;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ and X³ are each independently halogen or C₁-C₃haloalkyl; and

X² is halogen or hydrogen;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above,

or a pharmaceutically acceptable salt thereof,

wherein

X¹ and X² are each independently chloro or fluoro; and

X³ is chloro or CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above, or a pharmaceutically acceptable saltthereof, wherein

X¹ and X² are each independently chloro or fluoro; and

X³ is chloro or CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent that is miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ and X² are each independently chloro or fluoro; and

X³ is chloro or CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ and X² are each independently chloro or fluoro; and

X³ is chloro or CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ and X² are each independently chloro or fluoro; and

X³ is chloro or CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one surfactant and/or at least one additionalpharmaceutically acceptable additive, excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ and X² are each independently chloro or fluoro; and

X³ is chloro or CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ and X² are each independently chloro or fluoro; and

X³ is chloro or CF₃;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above, or a pharmaceutically acceptable saltthereof

wherein

X¹ and X³ are each chloro; and

X² is fluoro or hydrogen;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above, or a pharmaceutically acceptable saltthereof, wherein

X¹ and X³ are each chloro; and

X² is fluoro or hydrogen;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent that is miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ and X³ are each chloro; and

X² is fluoro or hydrogen;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above,

or a pharmaceutically acceptable salt thereof,

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof,

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent that is miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one surfactant and optionally at least oneadditional pharmaceutically acceptable additive, excipient or mixturesthereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is aC₁-C₆alcohol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (Ic) as described above, or a pharmaceuticallyacceptable salt thereof;

wherein

X¹ is chloro;

X² is fluoro; and

X³ is CF₃;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above, or a pharmaceutically acceptable saltthereof, wherein

X¹ and X³ are chloro; and

X² is fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof;

wherein

X¹ and X³ are chloro; and

X² is fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent that is miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹ and X³ are chloro; and

X² is fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹ and X³ are chloro; and

X² is fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹ and X³ are chloro; and

X² is fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one surfactant, and optionally at least oneadditional pharmaceutically acceptable additive, excipient or mixturesthereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹ and X³ are chloro; and

X² is fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, at least one co-solvent wherein said co-solvent is aC₈-C₁₀ triglyceride, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹ and X³ are chloro; and

X² is fluoro;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, at least one co-solvent wherein said co-solvent isethanol, isopropanol, benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above,

or a pharmaceutically acceptable salt thereof,

wherein

X¹, X² and X³ are each chloro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹, X² and X³ are each chloro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent that is miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹, X² and X³ are each chloro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹, X² and X³ are each chloro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol, aglycol ether (e.g., including, but limited to, diethyleneglycolmonoethyl ether, butyl diglycol, dipropylene glycol n-butyl ether,ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), glycerol, propyleneglycol, cyclic carbonates (e.g., propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide,dimethylsulfoxide or glycerol formal, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹, X² and X³ are each chloro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, a co-solvent, wherein the co-solvent is benzyl alcohol,benzyl benzoate, ethyl acetate, triacetin, lipids, C₈-C₁₀ triglycerides(e.g. MIGLYOL® 810 and MIGLYOL®812), C₈-C₁₀ triglycerides combined withlinoleic acid (e.g. MIGLYOL® 818), C₈-C₁₀ triglycerides combined withsuccinic acid (e.g. MIGLYOL® 829), propylene glycol diester of C₈-C₁₀fatty acids (e.g. MIGLYOL® 840), castor oil, cottonseed oil, sesame oil,soybean oil and safflower oil, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one surfactant, and optionally at least oneadditional pharmaceutically acceptable additive, excipient or mixturesthereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹, X² and X³ are each chloro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a neutral oil;

c) optionally, a co-solvent, wherein the co-solvent is a C₁-C₆alcohol,benzyl alcohol, or a combination thereof;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as shown above, or a pharmaceutically acceptable saltthereof, wherein

X¹, X² and X³ are each independently chloro or fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹, X² and X³ are each independently chloro or fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent, wherein said co-solvent is apolar solvent that is miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

In another embodiment, the present invention provides for a long-actinginjectable composition for the treatment and/or prevention (prophylaxis)of parasitic infections and infestations in or on animals comprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (Ic) as described above, or a pharmaceutically acceptable saltthereof

wherein

X¹, X² and X³ are each independently chloro or fluoro;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is notmiscible with water or only partially soluble in water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof;

wherein no other pharmaceutically acceptable polymers are present.

The compounds of formula (I) through formula (VIa) can exist asstereoisomers, and each individual stereoisomer present are encompassedby the structural formulas depicted herein. The various stereoisomersinclude enantiomers, diastereomers and atop isomers. For avoidance ofdoubt, when an isoxazoline compound (e.g. any of the isoxazoline activeagents as described herein) includes two or more stereoisomers (e.g. an(S)- and (R)-enantiomers), the formulae depicted herein that does notexplicitly include stereochemical configurations encompasses each of thepossible stereoisomers. One of skill in the art will understand that onestereoisomer of an active isoxazoline compound may be more active and/ormay exhibit beneficial properties relative to the other enantiomer. Inaddition, the skilled person in the art knows how to separate, enrich,and/or selectively prepare a stereoisomer of the isoxazoline compoundsdescribed herein. The isoxazoline compounds described herein contain achiral quaternary carbon atom in the five-membered isoxazoline ring(shown by the asterisk (*) in the structures below); therefore, thecompounds will contain at least two possible stereoisomers. As anexample for the compounds of formula (Ia), the two possiblestereoisomers resulting from the quaternary carbon are shown as formulae(S)-Ia and (R)-Ia:

The compound of formula (S)-Ia above has the (S) configuration at thechiral carbon atom and the compound of formula (R)-Ia has the (R)configuration. Molecular depictions drawn herein follow standardconventions for depicting stereochemistry. To indicate stereoconfiguration, bonds rising from the plane of the drawing and towardsthe viewer are denoted by solid wedges wherein the broad end of thewedge is attached to the atom rising from the plane of the drawingtowards the viewer. Bonds going below the plane of the drawing and awayfrom the viewer are denoted by dashed wedges wherein the narrow end ofthe wedge is attached to the atom further away from the viewer. Constantwidth lines indicate bonds with a direction opposite or neutral relativeto bonds shown with solid or dashed wedges; constant width lines alsodepict bonds in molecules or parts of molecules in which no particularstereo configuration is intended to be specified.

In one embodiment of the invention, the more biologically activeenantiomer is believed to be formula (S)-Ia. Similarly, the morebiologically active enantiomers of isoxazoline compounds of formula(Ib), (Ic) and (II) to (VIa) are believed to have the (S) configurationat the chiral carbon of the isoxazoline ring. In certain embodiments, anisoxazoline compound of the invention, or compositions comprising thecompound, are enriched in an enantiomer that displays significant invitro and in vivo activity (the eutomer) with a favorable toxicityprofile relative to a compound or a composition enriched with the othercorresponding enantiomer that displays significantly less in vitro andin vivo activity (the distomer).

When enantiomerically enriched, one enantiomer is present in greateramounts than the other, and the extent of enrichment may be defined byan expression of enantiomeric excess (“ee”), which is defined as (2x−1)100%, where x is the mole fraction of the dominant enantiomer in themixture (e.g., an ee of 20% corresponds to a 60:40 ratio ofenantiomers). In some embodiments, the compositions of the inventioncomprise compounds that have at least a 50% enantiomeric excess. Inother embodiments, the compositions of the invention comprise compoundsthat have at least a 75% enantiomeric excess, at least a 90%enantiomeric excess, or at least a 94% enantiomeric excess of the moreactive isomer. Of particular note are enantiomerically pure embodimentsof the more active isomer (the eutomer).

Compounds of this invention may also exist as one or more conformationalisomers due to restricted rotation about the amide bond bonded to thearyl or heteroaryl ring (e.g. the amide bonded to the naphthyl group informula (I)). This invention comprises mixtures of conformationalisomers. In addition, this invention includes compounds that areenriched in one conformer relative to others.

It will be appreciated that in addition to the compounds of formula(Ia), the other isoxazoline compounds of formula (I), formula (Ib),formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025),formula (II-2.001) to formula (II-018), formula (III), formula (IV),formula (V), formula (Va), formula (VI) and formula (VIa) will also haveat least two possible enantiomers as a result of the quaternary carbonatom on the isoxazoline ring. In addition, certain compounds may includeother chiral centers in one or more substituents.

This invention comprises racemic mixtures, for example, equal amounts ofthe enantiomers of formulae (I) to (VIa). The invention also includescompounds of formula (I), formula (Ia), formula (Ib), formula (Ic),formula (II), formula (II-1.1001) to formula (II-1.025), formula(II-2.001) to formula (II-018), formula (III), formula (IV), formula(V), formula (Va), formula (VI) or formula (VIa), that are enriched inone enantiomer compared to the racemic mixture. Also included are theessentially pure enantiomers of the compounds of formula (I), formula(Ia), formula (Ib), formula (Ic), formula (II), formula (II-1.1001) toformula (II-1.025), formula (II-2.001) to formula (II-018), formula(III), formula (IV), formula (V), formula (Va), formula (VI) or formula(VIa).

Hence, in one embodiment, the long-acting injectable compositions ofpresent invention comprise an antiparasitic effective amount of at leastone isoxazoline of formula (I), formula (Ia), formula (Ib), formula(Ic), formula (II), formula (II-1.1001) to formula (II-1.025), formula(II-2.001) to formula (II-018), formula (III), formula (IV), formula(V), formula (Va), formula (VI) or formula (VIa), which is substantiallyenriched in one enantiomer, or a pharmaceutically acceptable saltthereof. The term “substantially enriched” means that the compound isenriched in a weight:weight ratio of at least about 1.5 or higher infavor of the desired enantiomer. In another embodiment, the long-actingcompositions of the invention comprise at least one isoxazoline compoundof formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II),formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula(II-018), formula (III), formula (IV), formula (V), formula (Va),formula (VI) or formula (VIa) that are enriched in one enantiomer in aweight:weight ratio of at least 2:1, at least 5:1 or at least 10:1. Inanother embodiment, the compositions comprise at least one compound offormula (I), formula (Ia), formula (Ib), formula (Ic), formula (II),formula (II-1.1001) to formula (II-1.025), formula (II-2.001) to formula(II-018), formula (III), formula (IV), formula (V), formula (Va),formula (VI) or formula (VIa), which is enriched in one enantiomer in aweight:weight ratio of at least 15:1 or at least 20:1, or apharmaceutically acceptable salt thereof. In an embodiment, theisoxazoline compounds of formula (I), formula (Ia), formula (Ib),formula (Ic), formula (II), formula (II-1.1001) to formula (II-1.025),formula (II-2.001) to formula (II-018), formula (III), formula (IV),formula (V), formula (Va), formula (VI) or formula (VIa) present in thecompositions of the invention are essentially pure enantiomers.

In another embodiment of the invention, the compositions comprise acompound of formula (I), formula (Ia), formula (Ib), formula (Ic),formula (II), formula (II-1.1001) to formula (II-1.025), formula(II-2.001) to formula (II-018), formula (III), formula (IV), formula(V), formula (Va), formula (VI) or formula (VIa), that is enriched inthe (S)-enantiomer in a weight:weight ratio is at least approximately1.5:1 or 2:1. In yet another embodiment, the compositions of theinvention comprise a compound of formula (I), formula (Ia), formula(Ib), formula (Ic), formula (II), formula (II-1.1001) to formula(II-1.025), formula (II-2.001) to formula (II-018), formula (III),formula (IV), formula (V), formula (Va), formula (VI) or formula (VIa),that is enriched in the (S)-enantiomer in a weight:weight ratio of atleast about 5:1 or greater. In still another embodiment, thecompositions of the invention comprise a compound of formula (I),formula (Ia), formula (Ib), formula (Ic), formula (II), formula(II-1.1001) to formula (II-1.025), formula (II-2.001) to formula(II-018), formula (III), formula (IV), formula (V), formula (Va),formula (VI) or formula (VIa), that is enriched in the (S)-enantiomer ina weight:weight ratio of at least approximately 10:1, 20:1, or greater.In still another embodiment, the compositions of the invention comprisea compound of formula (I), formula (Ia), formula (Ib), formula (Ic),formula (II), formula (II-1.1001) to formula (II-1.025), formula(II-2.001) to formula (II-018), formula (III), formula (IV), formula(V), formula (Va), formula (VI) or formula (VIa), that is essentiallythe pure (S)-enantiomer.

In one embodiment, the compositions of the invention comprise a compoundof formula (I), (Ia), (Ib) or (Ic) that is substantially enriched in anenantiomer. In another embodiment, the long-acting injectablecompositions of the invention comprise a compound of formula (I), (Ia),(Ib) or (Ic) that is substantially enriched in the (S)-enantiomer. Inanother embodiment, the long-acting injectable compositions of theinvention comprise a compound of formula (I), (Ia), (Ib) or (Ic) that issubstantially enriched in the (R)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the(S)-enantiomer in a weight:weight ratio is at least approximately 1.5:1or 2:1 or greater. In yet another embodiment, the compositions of theinvention comprise a compound of formula (I), (Ia), (Ib) or (Ic) that isenriched in the (S)-enantiomer in a weight:weight ratio of at leastabout 5:1 or greater. In still another embodiment, the compositions ofthe invention comprise a compound of formula (I), (Ia), (Ib) or (Ic)that is enriched in the (S)-enantiomer in a weight:weight ratio of atleast approximately 10:1, 20:1, or greater. In still another embodiment,the compositions of the invention comprise a compound of formula (I),(Ia), (Ib) or (Ic) that is essentially the pure (S)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of formula (I), (Ia), (Ib) or (Ic) that is enriched in the(R)-enantiomer in a weight:weight ratio is at least approximately 2:1 orgreater. In yet another embodiment, the compositions of the inventioncomprise a compound of formula (I), (Ia), (Ib) or (Ic) that is enrichedin the (R)-enantiomer in a weight:weight ratio of at least about 5:1 orgreater. In still another embodiment, the compositions of the inventioncomprise a compound of formula (I), (Ia), (Ib) or (Ic) that is enrichedin the (R)-enantiomer in a weight:weight ratio of at least about 10:1,20:1, or greater. In still another embodiment, the compositions of theinvention comprise a compound of formula (I), (Ia), (Ib) or (Ic) that isessentially the pure (R)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of formula (II), formula (II-1.1001) to formula (II-1.025),formula (II-2.001) to formula (II-018), formula (III), formula (IV),formula (V), formula (Va), formula (VI) or formula (VIa), that isenriched in the (R)-enantiomer in a weight:weight ratio is at leastapproximately 2:1 or greater.

In yet another embodiment, the compositions of the invention comprise acompound of formula (II), formula (II-1.1001) to formula (II-1.025),formula (II-2.001) to formula (II-018), formula (III), formula (IV),formula (V), formula (Va), formula (VI) or formula (VIa), that isenriched in the (R)-enantiomer in a weight:weight ratio of at leastabout 5:1 or greater. In still another embodiment, the compositions ofthe invention comprise a compound of formula (II), formula (II-1.1001)to formula (II-1.025), formula (II-2.001) to formula (II-018), formula(III), formula (IV), formula (V), formula (Va), formula (VI) or formula(VIa), that is enriched in the (R)-enantiomer in a weight:weight ratioof at least approximately 10:1, 20:1, or greater. In still anotherembodiment, the compositions of the invention comprise a compound offormula (II), formula (II-1.1001) to formula (II-1.025), formula(II-2.001) to formula (II-018), formula (III), formula (IV), formula(V), formula (Va), formula (VI) or formula (VIa), that is essentiallythe pure (R)-enantiomer.

In another embodiment, the long-acting injectable compositions ofpresent invention comprise an antiparasitic effective amount of at leastone isoxazoline disclosed in WO 2007/079162, WO 2007/075459 and US2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO2009/002809, WO 2009/024541, WO 2005/085216 and US 2007/0066617 WO2008/122375, WO 2014/439475 A1 and WO2012 120135A1, all of which areincorporated herein by reference in their entirety.

In yet another embodiment, the long-acting injectable compositions ofpresent invention comprise an antiparasitic effective amount of at leastone isoxazoline compound described in WO 2009/02451A2 and WO2011/075591A1, both incorporated herein by reference in their entirety.

In yet another embodiment, the long-acting injectable compositions ofpresent invention comprise an antiparasitic effective amount of at leastone isoxazoline which is compound 11-1 described in WO 2009/02451A2,which has the structure:

In one embodiment, the compositions of the invention may comprise about0.5 to about 50% (w/v) of an isoxazoline active agent of any of formulae(I), (Ia), (Ic), (II), (III), (IV), (V), (Va), (VI) or (VIa), or apharmaceutically acceptable salt thereof, either as a racemic mixture orenriched in an enantiomer as described above. In another embodiment, thecompositions of the invention may comprise about 1 to about 40% (w/v) ofan isoxazoline active agent of any of formulae (I), (Ia), (Ib), (Ic),(II), (III), (IV), (V), (Va), (VI) or (VIa), or a pharmaceuticallyacceptable salt thereof. In yet another embodiment, the compositions ofthe invention may comprise about 1 to about 30% (w/v), about 1 to about20% (w/v) or about 1 to about 15% (w/v) of an isoxazoline active agentof any of formulae (I), (Ia), (Ib), (Ic), (II), (III), (IV), (V), (Va),(VI) or (Via), or a pharmaceutically acceptable salt thereof. In anotherembodiment, the compositions of the invention may comprise about 0.5 toabout 10% (w/v) or about 0.5% to about 5% (w/v) of an isoxazoline activeagent of any of formulae (I), (Ia), (Ib), (Ic), (II), (III), (IV), (V),(Va), (VI) or (VIa), or a pharmaceutically acceptable salt thereof.

In another embodiment, the compositions of the invention may compriseabout 5 to about 40% (w/v) or about 5 to about 30% (w/v) of anisoxazoline active agent, or a pharmaceutically acceptable salt thereof.In another embodiment, the compositions may comprise about 10% to about40% (w/v) of an isoxazoline active agent, or a pharmaceuticallyacceptable salt thereof. In yet another embodiment, the compositions ofthe invention may comprise about 15% to about 40% (w/v), about 15% toabout 35% (w/v) or about 15% to about 30% (w/v) of an isoxazolinecompound, or a pharmaceutically acceptable salt thereof.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prevention of parasiticinfections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formula I to VIa describedabove), or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In another embodiment the present invention provides for long-actinginjectable compositions for the treatment and/or prevention of parasiticinfections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formula I to VIa describedabove), or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prevention of parasiticinfections and infestations in or on animals comprising:

a) about 5 to 30% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formula I to VIa describedabove), or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prevention of parasiticinfections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formula I to VIa describedabove), or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein saidco-solvent is a polar solvent that is miscible with water;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In another embodiment the present invention provides for long-actinginjectable compositions for the treatment and/or prevention of parasiticinfections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formula I to VIa describedabove), or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein saidco-solvent is a polar solvent that is miscible with water;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prevention of parasiticinfections and infestations in or on animals comprising:

a) about 5 to 30% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formula I to VIa describedabove), or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein saidco-solvent is a polar solvent that is miscible with water;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (e.g., a compound of formulae I-VIa), such as, a compound of theformula:

wherein X¹, X² and X³ are independently chloro, fluoro or CF₃;

wherein X¹, X² and X³ are independently chloro, fluoro or CF₃;

wherein X¹, X² and X³ are independently chloro, fluoro or CF₃;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of a co-solvent, wherein theco-solvent is a C₁-C₆alcohol, a glycol ether (e.g., including, butlimited to, diethyleneglycol monoethyl ether, butyl diglycol,dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether,propylene glycol monomethyl ether, propylene glycol monoethyl ether, andthe like), glycerol, propylene glycol, cyclic carbonates (e.g.,propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethylisosorbide (DMI), dimethylacetamide, dimethylsulfoxide or glycerolformal, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa)or (S)-VIa as shown above; or a pharmaceutically acceptable saltthereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is a C₁-C₆alcohol, a glycol ether (e.g., including, butlimited to, diethyleneglycol monoethyl ether, butyl diglycol,dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether,propylene glycol monomethyl ether, propylene glycol monoethyl ether, andthe like), glycerol, propylene glycol, cyclic carbonates (e.g.,propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethylisosorbide (DMI), dimethylacetamide, dimethylsulfoxide or glycerolformal, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va)or (S)-VIa as shown above;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is a C₁-C₆alcohol, a glycol ether (e.g., including, butlimited to, diethyleneglycol monoethyl ether, butyl diglycol,dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether,propylene glycol monomethyl ether, propylene glycol monoethyl ether, andthe like), glycerol, propylene glycol, cyclic carbonates (e.g.,propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethylisosorbide (DMI), dimethylacetamide, dimethylsulfoxide or glycerolformal, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va)or (S)-VIa as shown above; or a pharmaceutically acceptable saltthereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is a C₁-C₆alcohol, a glycol ether (e.g., including, butlimited to, diethyleneglycol monoethyl ether, butyl diglycol,dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether,propylene glycol monomethyl ether, propylene glycol monoethyl ether, andthe like), glycerol, propylene glycol, cyclic carbonates (e.g.,propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethylisosorbide (DMI), dimethylacetamide, dimethylsulfoxide or glycerolformal, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va)or (S)-VIa as shown above, or a pharmaceutically acceptable saltthereof;

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 40% (w/v) of a co-solvent, wherein theco-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin,lipids, C₈-C₁₀ triglycerides (e.g. MIGLYOL®810 and MIGLYOL®812), C₈-C₁₀triglycerides combined with linoleic acid (e.g. MIGLYOL®818), C₈-C₁₀triglycerides combined with succinic acid (e.g. MIGLYOL® 829), propyleneglycol diester of C₈-C₁₀ fatty acids (e.g. MIGLYOL® 840), castor oil,cottonseed oil, sesame oil, soybean oil and safflower oil, or acombination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va)or (S)-VIa as shown above; or a pharmaceutically acceptable saltthereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 5% to 40% (w/v) of co-solvent, wherein theco-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin,lipids, C₈-C₁₀ triglycerides (e.g. MIGLYOL®810 and MIGLYOL®812), C₈-C₁₀triglycerides combined with linoleic acid (e.g. MIGLYOL®818), C₈-C₁₀triglycerides combined with succinic acid (e.g. MIGLYOL® 829), propyleneglycol diester of C₈-C₁₀ fatty acids (e.g. MIGLYOL® 840), castor oil,cottonseed oil, sesame oil, soybean oil and safflower oil, or acombination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (Va)or (S)-VIa as shown above; or a pharmaceutically acceptable saltthereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin,lipids, C₈-C₁₀ triglycerides (e.g. MIGLYOL®810 and MIGLYOL®812), C₈-C₁₀triglycerides combined with linoleic acid (e.g. MIGLYOL®818), C₈-C₁₀triglycerides combined with succinic acid (e.g. MIGLYOL® 829), propyleneglycol diester of C₈-C₁₀ fatty acids (e.g. MIGLYOL® 840), castor oil,cottonseed oil, sesame oil, soybean oil and safflower oil, or acombination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ are independentlychloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa)or (S)-VIa as shown above;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is benzyl alcohol, benzyl benzoate, ethyl acetate, triacetin,lipids, C₈-C₁₀ triglycerides (e.g. MIGLYOL®810 and MIGLYOL®812), C₈-C₁₀triglycerides combined with linoleic acid (e.g. MIGLYOL®818), C₈-C₁₀triglycerides combined with succinic acid (e.g. MIGLYOL® 829), propyleneglycol diester of C₈-C₁₀ fatty acids (e.g. MIGLYOL® 840), castor oil,cottonseed oil, sesame oil, soybean oil and safflower oil, or acombination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition. In certainembodiments the present invention provides for long-acting injectablecompositions for the treatment and/or prophylaxis of parasiticinfections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa asshown above, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of a co-solvent, wherein theco-solvent is a C₁-C₆alcohol, benzyl alcohol, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa asshown above, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is a C₁-C₆alcohol, benzyl alcohol, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa asshown above, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is a C₁-C₆alcohol, benzyl alcohol, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ are independently chloro,fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (S)-Va, (VIa) or (S)-VIa asshown above, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is a C₁-C₆alcohol, benzyl alcohol, or a combination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 40% (w/v) of a co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer which is a liquidPEG;

c) optionally, about 1% to 40% (w/v) of a co-solvent, wherein saidco-solvent is a C₈-C₁₀ triglyceride, benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, about 1% to 40% (w/v) of a co-solvent, wherein saidco-solvent is ethanol, isopropanol, benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 40% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or aneutral oil;

c) optionally, about 1% to 20% (w/v) of a co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG and/or aneutral oil;

c) optionally, about 1% to 20% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or aneutral oil;

c) optionally, about 1% to 20% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG and/or aneutral oil;

c) optionally, about 1% to 20% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 1% to 20% (w/v) of a co-solvent wherein saidco-solvent is a C₈-C₁₀ triglyceride, benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of at least onepharmaceutically acceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) at least one neutral oil, wherein said neutral oil is a C₈-C₁₀triglyceride;

c) optionally, about 1% to 20% (w/v) at least one co-solvent, whereinsaid co-solvent is ethanol, isopropanol, benzyl alcohol, or acombination thereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of at least onepharmaceutically acceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 2% to 15% (w/v) of a co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 2% to 15% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 20% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 2% to 15% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 15% (w/v) of an isoxazoline active agent of the formula(Ia), (S)-Ia, (Ic), wherein X¹ is chloro, X² is fluoro and X³ is CF₃; or(S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, as shownabove, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 2% to 15% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 15% (w/v) of an isoxazoline active agent of the formula(S)-Ia or (S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, asshown above, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 2% to 15% (w/v) of a co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 5 to 20% (w/v) of an isoxazoline active agent of the formula(S)-Ia or (S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃; asshown above, or a pharmaceutically acceptable salt thereof;

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 2% to 15% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 5 to 15% (w/v) of an isoxazoline active agent of the formula(S)-Ia or (S)-Ic, wherein X¹ is chloro, X² is fluoro and X³ is CF₃, asshown above, or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof,

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 2% to 10% (w/v) of co-solvent, wherein theco-solvent is ethanol, isopropanol or benzyl alcohol, or a combinationthereof;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

In certain embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 0.5 to 30% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formulae I to VIadescribed above), such as, a compound of the formula (Ia), (S)-Ia,(R)-Ia, (Ic), wherein X¹, X² and X³ are independently chloro, fluoro orCF₃; (S)-Ic, wherein X¹, X² and X³ are independently chloro, fluoro orCF₃; (R)-Ic wherein X¹, X² and X³ are independently chloro, fluoro orCF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa asshown above; or a pharmaceutically acceptable salt thereof:

b) pharmaceutically acceptable polymer which is a liquid PEG and/or apharmaceutically acceptable neutral oil;

c) optionally, about 5% to 40% (w/v) of co-solvent selected from thegroup consisting of ethanol and isopropanol;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or neutral oil is present in the overall composition in aproportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 30% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of formulae I to VIadescribed above), such as, a compound of the formula (Ia), (S)-Ia,(R)-Ia, (Ic), wherein X¹, X² and X³ are independently chloro, fluoro orCF₃; (S)-Ic, wherein X¹, X² and X³ are independently chloro, fluoro orCF₃; (R)-Ic wherein X¹, X² and X³ are independently chloro, fluoro orCF₃; (III), (S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa asshown above; or a pharmaceutically acceptable salt thereof:

b) pharmaceutically acceptable polymer which is a liquid PEG and/or aneutral oil;

c) optionally, about 5% to 40% (w/v) of co-solvent selected from thegroup consisting of ethanol and isopropanol;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or the neutral oil is present in the overall compositionin a proportion representing the complement to 100% of the composition.

In yet other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 1 to 20% (w/v) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of formulae I-VIa), such as, acompound of the

formula (Ia), (S)-Ia, (R)-Ia, (Ic), wherein X¹, X² and X³ areindependently chloro, fluoro or CF₃; (S)-Ic, wherein X¹, X² and X³ areindependently chloro, fluoro or CF₃; (R)-Ic wherein X¹, X² and X³ areindependently chloro, fluoro or CF₃; (III), (S)-III, (IV), (S)-IV, (Va),(S)-Va, (VIa) or (S)-VIa as shown above; or a pharmaceuticallyacceptable salt thereof:

b) pharmaceutically acceptable polymer which is a liquid PEG and/or aneutral oil;

c) optionally, about 5% to 40% (w/v) of co-solvent selected from thegroup consisting of ethanol and isopropanol;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG and/or the neutral oil is present in the overall compositionin a proportion representing the complement to 100% of the composition.

In other embodiments the present invention provides for long-actinginjectable compositions for the treatment and/or prophylaxis ofparasitic infections and infestations in or on animals comprising:

a) about 5 to 20% (w/v) or about 5 to about 15% (w/v) of an isoxazolineactive agent, such as, for example, any of the isoxazoline compoundsprovided for in the embodiments above (e.g., a compound of formulaeI-VIa), such as, a compound of the formula (Ia), (S)-Ia, (R)-Ia, (Ic),wherein X¹, X² and X³ are independently chloro, fluoro or CF₃; (S)-Ic,wherein X¹, X² and X³ are independently chloro, fluoro or CF₃; (R)-Icwherein X¹, X² and X³ are independently chloro, fluoro or CF₃; (III),(S)-III, (IV), (S)-IV, (Va), (S)-Va, (VIa) or (S)-VIa as shown above; ora pharmaceutically acceptable salt thereof:

b) pharmaceutically acceptable polymer which is a liquid PEG;

c) optionally, about 5% to 40% (w/v) of co-solvent selected from thegroup consisting of ethanol and isopropanol;

d) optionally, about 0.01% to about 2.0% (w/v) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/v) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof;

wherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.

Another embodiment of the present invention is a long-acting injectablecomposition for the treatment and/or prevention of parasitic infectionsand infestations in or on animals consisting essentially of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of formulae I-VIa), andoptionally at least one additionally active agent as identified in thisapplication;

b) a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) optionally, at least one co-solvent wherein said co-solvent is apolar solvent miscible with water;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

Another embodiment of the present invention is a long-acting injectablecomposition for the treatment and/or prevention of parasitic infectionsand infestations in or on animals consisting of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of formulae I-VIa), andoptionally at least one additionally active agent as identified in thisapplication;

b) a liquid PEG and/or a pharmaceutically acceptable neutral oil;

c) at least one co-solvent wherein said co-solvent is not miscible withwater;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In this disclosure and in the claims, terms such as “comprises,”“comprising,” “containing” and “having” and the like can have themeaning ascribed to them in U.S. Patent law and can mean “includes,”“including,” and the like; “consisting essentially of” or “consistsessentially” likewise has the meaning ascribed in U.S. Patent law andthe term is open-ended, allowing for the presence of more than thatwhich is recited so long as basic or novel characteristics of that whichis recited is not changed by the presence of more than that which isrecited, but excludes prior art embodiments. The term “consisting of”excludes any element, step or ingredient not specified in the claims.

Definitions

Terms used herein will have their customary meaning in the art unlessspecified otherwise. The organic moieties mentioned in the definitionsof the variables of formula (I) are—like the term halogen—collectiveterms for individual listings of the individual group members. Theprefix C_(n)-C_(m) indicates in each case the possible number of carbonatoms in the group.

The term “animal” is used herein to include all mammals, birds and fishand also include all vertebrate animals. Animals include, but are notlimited to, cats, dogs, cattle, chickens, cows, deer, goats, horses,llamas, pigs, sheep and yaks. It also includes an individual animal inall stages of development, including embryonic and fetal stages. In someembodiments, the animal will be a non-human animal.

The term “essentially pure” is used herein to indicate that a compoundor an enantiomer is at least about 90% pure, at least about 95%, atleast about 98% pure, or higher.

The term “alkyl” refers to saturated straight, branched, primary,secondary or tertiary hydrocarbons, including those having 1 to 20atoms. In some embodiments, alkyl groups will include C₁-C₁₂, C₁-C₁₀,C₁-C₈, C₁-C₆ or C₁-C₄ alkyl groups. Examples of C₁-C₁₀ alkyl include,but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,2-ethylhexyl, nonyl and decyl and their isomers. C₁-C₄-alkyl means forexample methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups or “cycloalkyl” include those with 3 to 10 carbonatoms having single or multiple condensed rings. In some embodiments,cycloalkyl groups include C₄-C₇ or C₃-C₄ cyclic alkyl groups.Non-limiting examples of cycloalkyl groups include adamantyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and the like.

The alkyl groups described herein can be unsubstituted or substitutedwith one or more moieties selected from the group consisting of alkyl,halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- ordialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido,thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl,sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine,thioester, thioether, acid halide, anhydride, oxime, hydrazine,carbamate, phosphoric acid, phosphate, phosphonate, or any other viablefunctional group that does not inhibit the biological activity of thecompounds of the invention, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Third Edition, 1999, hereby incorporated by reference.

Terms including the term “alkyl” such as “alkylcycloalkyl,”“cycloalkylalkyl,” “alkylamino,” or “dialkylamino” will be understood tocomprise an alkyl group as defined above linked to the other functionalgroup, where the group is linked to the compound through the last grouplisted, as understood by those of skill in the art.

The term “alkenyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon double bond. In some embodiments,alkenyl groups may include C₂-C₂₀ alkenyl groups. In other embodiments,alkenyl includes C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkenyl groups.In one embodiment of alkenyl, the number of double bonds is 1-3, inanother embodiment of alkenyl, the number of double bonds is one or two.Other ranges of carbon-carbon double bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. “C₂-C₁₀-alkenyl” groups may include more than one double bondin the chain. Examples include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

“Alkynyl” refers to both straight and branched carbon chains which haveat least one carbon-carbon triple bond. In one embodiment of alkynyl,the number of triple bonds is 1-3; in another embodiment of alkynyl, thenumber of triple bonds is one or two. In some embodiments, alkynylgroups include from C₂-C₂₀ alkynyl groups. In other embodiments, alkynylgroups may include C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkynyl groups.Other ranges of carbon-carbon triple bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. For example, the term “C₂-C₁₀-alkynyl” as used herein refersto a straight-chain or branched unsaturated hydrocarbon group having 2to 10 carbon atoms and containing at least one triple bond, such asethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl,n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl,n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl,n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl,3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl,n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl,n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl,n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl,3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl,4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term “haloalkyl” refers to an alkyl group, as defined herein, whichis substituted by one or more halogen atoms. For example C₁-C₄-haloalkylincludes, but is not limited to, chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl andthe like.

The term “haloalkenyl” refers to an alkenyl group, as defined herein,which is substituted by one or more halogen atoms.

The term “haloalkynyl” refers to an alkynyl group, as defined herein,which is substituted by one or more halogen atoms.

“Alkoxy” refers to alkyl-O—, wherein alkyl is as defined above.Similarly, the terms “alkenyloxy,” “alkynyloxy,” “haloalkoxy,”“haloalkenyloxy,” “haloalkynyloxy,” “cycloalkoxy,” “cycloalkenyloxy,”“halocycloalkoxy,” and “halocycloalkenyloxy” refer to the groupsalkenyl-O—, alkynyl-O—, haloalkyl-O—, haloalkenyl-O—, haloalkynyl-O—,cycloalkyl-O—, cycloalkenyl-O—, halocycloalkyl-O—, andhalocycloalkenyl-O—, respectively, wherein alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, andhalocycloalkenyl are as defined above. Examples of C₁-C₆-alkoxy include,but are not limited to, methoxy, ethoxy, C₂H₅—CH₂O—, (CH₃)₂CHO—,n-butoxy, C₂H₅—CH(CH₃)O—, (CH₃)₂CH—CH₂O—, (CH₃)₃CO—, n-pentoxy,1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy,1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxyand the like.

The term “alkylthio” refers to alkyl-S—, wherein alkyl is as definedabove. Similarly, the terms “haloalkylthio,” “cycloalkylthio,” and thelike, refer to haloalkyl-S— and cycloalkyl-S— where haloalkyl andcycloalkyl are as defined above.

The term “alkylsulfinyl” refers to alkyl-S(O)—, wherein alkyl is asdefined above. Similarly, the term “haloalkylsulfinyl” refers tohaloalkyl-S(O)— where haloalkyl is as defined above.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—, wherein alkyl is asdefined above. Similarly, the term “haloalkylsulfonyl” refers tohaloalkyl-S(O)₂— where haloalkyl is as defined above.

The term alkylamino and dialkylamino refer to alkyl-NH— and (alkyl)₂N—where alkyl is as defined above. Similarly, the terms “haloalkylamino”refers to haloalkyl-NH— where haloalkyl is as defined above.

The terms “alkylcarbonyl,” “alkoxycarbonyl,” “alkylaminocarbonyl,” and“dialkylaminocarbonyl” refer to alkyl-C(O)—, alkoxy-C(O)—,alkylamino-C(O)— and dialkylamino-C(O)— where alkyl, alkoxy, alkylaminoand dialkylamino are as defined above.

Similarly, the terms “haloalkylcarbonyl,” “haloalkoxycarbonyl,”“haloalkylaminocarbonyl,” and “dihaloalkylaminocarbonyl” refer to thegroups haloalkyl-C(O)—, haloalkoxy-C(O)—, haloalkylamino-C(O)— anddihaloalkylamino-C(O)— where haloalkyl, haloalkoxy, haloalkylamino anddihaloalkylamino are as defined above.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring or multiple condensed rings. In someembodiments, aryl groups include C₆-C₁₀ aryl groups. Aryl groupsinclude, but are not limited to, phenyl, biphenyl, naphthyl,tetrahydronaphtyl, phenylcyclopropyl and indanyl. Aryl groups may beunsubstituted or substituted by one or more moieties selected fromhalogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl,halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy,haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy,cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio,haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl,alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl,haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl,haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino,alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, ortrialkylsilyl.

The terms “aralkyl” or “arylalkyl” refers to an aryl group that isbonded to the parent compound through a diradical alkylene bridge,(—CH₂-)_(n), where n is 1-12 and where “aryl” is as defined above.

“Heteroaryl” refers to a monovalent aromatic group of from 1 to 15carbon atoms, preferably from 1 to 10 carbon atoms, having one or moreoxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfurheteroatoms may optionally be oxidized. Such heteroaryl groups can havea single ring (e.g., pyridyl or furyl) or multiple condensed ringsprovided that the point of attachment is through a heteroaryl ring atom.Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinnyl, furanyl, thiophenyl, furyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl benzofuranyl,and benzothiophenyl. Heteroaryl rings may be unsubstituted orsubstituted by one or more moieties as described for aryl above.

“Heterocyclyl,” “heterocyclic” or “heterocyclo” refer to fully saturatedor unsaturated, cyclic groups, for example, 3 to 7 membered monocyclicor 4 to 7 membered monocyclic; 7 to 11 membered bicyclic, or 10 to 15membered tricyclic ring systems, which have one or more oxygen, sulfuror nitrogen heteroatoms in ring, preferably 1 to 4 or 1 to 3heteroatoms. The nitrogen and sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom ofthe ring or ring system and may be unsubstituted or substituted by oneor more moieties as described for aryl groups above.

Exemplary monocyclic heterocyclic groups include, but are not limitedto, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl,4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include, but are not limited to,indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

Halogen means the atoms fluorine, chlorine, bromine and iodine. Thedesignation of “halo” (e.g. as illustrated in the term haloalkyl) refersto all degrees of substitutions from a single substitution to a perhalosubstitution (e.g. as illustrated with methyl as chloromethyl (—CH₂Cl),dichloromethyl (—CHCl₂), trichloromethyl (—CCl₃)).

By the term “enriched” is meant when the weight:weight ratio is at leastapproximately 1.05 or higher in favor of the enantiomer that displayssignificant in vitro and in vivo activity (the eutomer).

Stereoisomers and Polymorphic Forms

As noted above, it will be appreciated by those of skill in the art thatcertain compounds within the compositions of the invention may exist andbe isolated as optically active and racemic forms. Compounds having oneor more chiral centers, including at a sulfur atom, may be present assingle enantiomers or diastereomers or as mixtures of enantiomers and/ordiastereomers. For example, it is well known in the art that sulfoxidecompounds may be optically active and may exist as single enantiomers orracemic mixtures. In addition, compounds within the compositions of theinvention may include one or more chiral centers, which results in atheoretical number of optically active isomers. Where compounds withinthe compositions of the invention include n chiral centers, thecompounds may comprise up to 2^(n) optical isomers. The presentinvention encompasses compositions comprising the specific enantiomersor diastereomers of each compound as well as mixtures of differentenantiomers and/or diastereomers of the compounds of the invention thatpossess the useful properties described herein. In addition, theinvention encompasses compositions comprising one or more conformationalisomers (e.g. rotamers) as well as mixtures of conformational isomers.Conformational isomers of the isoxazoline compounds may be produced by arestriction of rotation about the amide bond bonded to the aryl orheteroaryl ring (e.g. the amide bonded to the naphthyl group in formula(I)). The optically active forms can be prepared by, for example,resolution of the racemic forms by selective crystallization techniques,by synthesis from optically active precursors, by chiral synthesis, bychromatographic separation using a chiral stationary phase or byenzymatic resolution.

In addition, the compounds within the compositions of the invention mayexist as hydrates or solvates, in which a certain stoichiometric amountof water or a solvent is associated with the molecule in the crystallineform. The compositions of the invention may include hydrates andsolvates of the active agents. In some embodiments, the compositions ofthe invention may include up to 15% (w/w), up to 20% (w/w), or up to 30%(w/w) of a particular solid form.

Salts

Also contemplated within the scope of the invention are acid or basesalts, where applicable, of the compounds of the invention provided forherein.

The term “acid salt” contemplates salts of the compounds with allpharmaceutically acceptable inorganic or organic acids. Inorganic acidsinclude mineral acids such as hydrohalic acids such as hydrobromic acidand hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid.Organic acids include all pharmaceutically acceptable aliphatic,alicyclic and aromatic carboxylic acids, dicarboxylic acids,tricarboxylic acids and fatty acids. In one embodiment of the acids, theacids are straight chain or branched, saturated or unsaturated C₁-C₂₀aliphatic carboxylic acids, which are optionally substituted by halogenor by hydroxyl groups, or C₆-C₁₂ aromatic carboxylic acids. Examples ofsuch acids are carbonic acid, formic acid, acetic acid, propionic acid,isopropionic acid, valeric acid, ca-hydroxy acids such as glycolic acidand lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid,and salicylic acid. Examples of dicarboxylic acids include oxalic acid,malic acid, succinic acid, tartaric acid, fumaric acid, and maleic acid.An example of a tricarboxylic acid is citric acid. Fatty acids includeall pharmaceutically acceptable saturated or unsaturated aliphatic oraromatic carboxylic acids having 4 to 24 carbon atoms. Examples includebutyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmiticacid, stearic acid, oleic acid, linoleic acid, linolenic acid, andphenylsteric acid. Other acids include gluconic acid, glycoheptonic acidand lactobionic acid.

The term “base salt” contemplates salts of the compounds with allpharmaceutically acceptable inorganic or organic bases, includinghydroxides, carbonates or bicarbonates of alkali metal or alkaline earthmetals. Salts formed with such bases include, for example, the alkalimetal and alkaline earth metal salts, including, but not limited to, asthe lithium, sodium, potassium, magnesium or calcium salts. Salts formedwith organic bases include the common hydrocarbon and heterocyclic aminesalts, which include, for example, ammonium salts (NH4⁺), alkyl- anddialkylammonium salts, and salts of cyclic amines such as the morpholineand piperidine salts.

In another embodiment, the long-acting injectable compositions ofpresent invention comprise an effective amount of at least oneisoxazoline or a pharmaceutically acceptable salt thereof in combinationat least one other active agent. In one embodiment, the long-actinginjectable compositions comprise an effective amount of at least oneisoxazoline compound of formula (I) to (VI), or a pharmaceuticallyacceptable salt thereof, in combination with at least one other activeagent that is systemically-active.

Additional veterinary/pharmaceutical active ingredients may be used withthe compositions of the invention. In some embodiments, the additionalactive agents may include, but are not limited to, acaricides,anthelmintics, anti-parasitics and insecticides. Anti-parasitic agentscan include both ectoparasiticidal and/or endoparasiticidal agents.

Veterinary pharmaceutical agents that may be included in thecompositions of the invention are well-known in the art (see e.g. Plumb'Veterinary Drug Handbook, 5^(th) Edition, ed. Donald C. Plumb, BlackwellPublishing, (2005) or The Merck Veterinary Manual, 9^(th) Edition,(January 2005)) and include but are not limited to acarbose,acepromazine maleate, acetaminophen, acetazolamide, acetazolamidesodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin,acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol,alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproicacid, aminopentamide hydrogen sulfate, aminophylline/theophylline,amiodarone, amitriptyline, amlodipine besylate, ammonium chloride,ammonium molybdate, amoxicillin, clavulanate potassium, amphotericin Bdesoxycholate, amphotericin B lipid-based, ampicillin, amprolium,antacids (oral), antivenin, apomorphione, apramycin sulfate, ascorbicacid, asparaginase, aspiring, atenolol, atipamezole, atracuriumbesylate, atropine sulfate, aurnofin, aurothioglucose, azaperone,azathioprine, azithromycin, baclofen, barbituates, benazepril,betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate,bleomycin sulfate, boldenone undecylenate, bromides, bromocriptinemesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanoltartrate, cabergoline, calcitonin salmon, calcitrol, calcium salts,captopril, carbenicillin indanyl sodium, carbimazole, carboplatin,carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium,cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetandisodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofursodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins,cephapirin, charcoal (activated), chlorambucil, chloramphenicol,chlordiazepoxide, chlordiazepoxide+/−clidinium bromide, chlorothiazide,chlorpheniramine maleate, chlorpromazine, chlorpropamide,chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine,ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin,clemastine fumarate, clenbuterol, clindamycin, clofazimine,clomipramine, claonazepam, clonidine, cloprostenol sodium, clorazepatedipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine,corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine,cyproheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D,dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate,deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressinacetate, desoxycorticosterone pivalate, detomidine, dexamethasone,dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral),dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazinecitrate, diethylstilbestrol (DES), difloxacin, digoxin,dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol/BAL,dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine,disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate,domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin,doxycycline, edetate calcium disodium.calcium EDTA, edrophoniumchloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin,ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin,epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynicacid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac,etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids(essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim,finasteride, fipronil, florfenicol, fluconazole, flucytosine,fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine,fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxaminemaleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin,gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon,glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine,glyburide, glycerin (oral), glycopyrrolate, gonadorelin, grisseofulvin,guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®), heparin,hetastarch, hyaluronate sodium, hydrazaline, hydrochlorothiazide,hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea,hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate,impenem-cilastatin sodium, imipramine, inamrinone lactate, insulin,interferon alfa-2a (human recombinant), iodide (sodium/potassium),ipecac (syrup), ipodate sodium, iron dextran, isoflurane, isoproterenol,isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin,ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose,leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine,lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU),lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine,meclizine, meclofenamic acid, medetomidine, medium chain triglycerides,medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin,meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin,methadone, methazolamide, methenamine mandelate/hippurate, methimazole,methionine, methocarbamol, methohexital sodium, methotrexate,methoxyflurane, methylene blue, methylphenidate, methylprednisolone,metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone,midazolam milbemycin oxime, mineral oil, minocycline, misoprostol,mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone,mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics,neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram,nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine,novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium,omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillinsodium, oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline,oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide,paromomycin sulfate, parozetine, pencillamine, general informationpenicillins, penicillin G, penicillin V potassium, pentazocine,pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline,pergolide mesylate, phenobarbital, phenoxybenzamine, pheylbutazone,phenylephrine, phenypropanolamine, phenytoin sodium, pheromones,parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine,pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril,potassium chloride, pralidoxime chloride, prazosin,prednisolone/prednisone, primidone, procainamide, procarbazine,prochlorperazine, propantheline bromide, Propionibacterium acnesinjection, propofol, propranolol, protamine sulfate, pseudoephedrine,psyllium hydrophilic mucilloid, pyridostigmine bromide, pyrilaminemaleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin,s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin,selegiline/1-deprenyl, sertraline, sevelamer, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate,somatotropin, sotalol, spectinomycin, spironolactone, stanozolol,streptokinase, streptozocin, succimer, succinylcholine chloride,sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline, terbutaline sulfate, testosterone,tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopentalsodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium,tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate,tocainide, tolazoline, telfenamic acid, topiramate, tramadol,trimcinolone acetonide, trientine, trilostane, trimepraxine tartratew/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid,vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil,vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarinsodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zincacetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the invention, arylpyrazole compounds such asphenylpyrazoles, known in the art may be combined with the isoxazolinecompounds in the long-acting injectable compositions of the invention.Examples of such arylpyrazole compounds include but are not limited tothose described in U.S. Pat. Nos. 6,001,384; 6,010,710; 6,083,519;6,096,329; 6,174,540; 6,685,954 and 6,998,131 (all of which areincorporated herein by reference, each assigned to Merial, Ltd., Duluth,Ga.).

In another embodiment of the invention, one or more macrocyclic lactonesor lactams, which act as an acaricide, anthelmintic agent and/orinsecticide, can be added to the compositions of the invention.

The macrocyclic lactones include, but are not limited to, avermectinssuch as abamectin, dimadectin, doramectin, emamectin, eprinomectin,ivermectin, latidectin, lepimectin, selamectin and ML-1,694,554, andmilbemycins such as milbemectin, milbemycin D, milbemycin oxime,moxidectin and nemadectin. Also included are the 5-oxo and 5-oximederivatives of said avermectins and milbemycins. Examples ofcombinations of arylpyrazole compounds with macrocyclic lactones includebut are not limited to those described in U.S. Pat. Nos. 6,426,333;6,482,425; 6,962,713 and 6,998,131 (all incorporated herein byreference—each assigned to Merial, Ltd., Duluth, Ga.).

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., or Albers-Schonberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alia, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054.

Macrocyclic lactones are either natural products or are semi-syntheticderivatives thereof. The structure of the avermectins and milbemycinsare closely related, e.g., by sharing a complex 16-membered macrocycliclactone ring. The natural product avermectins are disclosed in U.S. Pat.No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosedin U.S. Pat. No. 4,199,569. Mention is also made of U.S. Pat. Nos.4,468,390, 5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390336, EP 0 002 916, and New Zealand Patent No. 237 086, inter alia.Naturally occurring milbemycins are described in U.S. Pat. No. 3,950,360as well as in the various references cited in “The Merck Index” 12^(th)ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, N.J.(1996). Latidectin is described in the “International NonproprietaryNames for Pharmaceutical Substances (INN)”, WHO Drug Information, vol.17, no. 4, pp. 263-286, (2003). Semisynthetic derivatives of theseclasses of compounds are well known in the art and are described, forexample, in U.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317,4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596,4,973,711, 4,978,677, 4,920,148 and EP 0 667 054.

In another embodiment of the invention, the invention comprises along-acting injectable composition comprising an isoxazoline compound incombination with systemically-acting compounds from a class ofacaricides or insecticides known as insect growth regulators (IGRs).Compounds belonging to this group are well known to the practitioner andrepresent a wide range of different chemical classes. These compoundsall act by interfering with the development or growth of the insectpests. Insect growth regulators are described, for example, in U.S. Pat.Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022or U.K. 2 140 010 as well as U.S. Pat. Nos. 6,096,329 and 6,685,954 (allincorporated herein by reference).

In one embodiment the IGR is a compound that mimics juvenile hormone.Examples of juvenile hormone mimics include azadirachtin, diofenolan,fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen,tetrahydroazadirachtin and4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one.

In an embodiment, the long-acting injectable compositions of presentinvention comprise an effective amount of at least one isoxazoline offormula (I) to (VIa), or a pharmaceutically acceptable salt thereof, incombination with methoprene or pyriproxyfen.

In another embodiment, the IGR compound is a chitin synthesis inhibitor.Chitin synthesis inhibitors include chlorofluazuron, cyromazine,diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumoron,lufenuron, tebufenozide, teflubenzuron, triflumuron, novaluron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylureaand 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

In yet another embodiment of the invention, adulticide insecticides andacaricides can also be added to the long-acting compositions of thepresent invention. These include pyrethrins (which include cinerin I,cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II andmixtures thereof) and pyrethroids, and carbamates including, but are notlimited to, benomyl, carbanolate, carbaryl, carbofuran, methiocarb,metolcarb, promacyl, propoxur, aldicarb, butocarboxim, oxamyl,thiocarboxime and thiofanox. In one embodiment, the compositions caninclude permethrin in combination with an isoxazoline active agent.

In some embodiments, the long-acting injectable compositions of thepresent invention may include one or more antinematodal agentsincluding, but not limited to, active agents in the benzimidazoles,imidazothiazoles, tetrahydropyrimidines, and organophosphate class ofcompounds. In some embodiments, benzimidazoles including, but notlimited to, thiabendazole, cambendazole, parbendazole, oxibendazole,mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole,cyclobendazole, febantel, thiophanate and its o,o-dimethyl analogue maybe included in the compositions.

In other embodiments, the long-acting injectable compositions of thepresent invention may include an imidazothiazole compounds including,but not limited to, tetramisole, levamisole and butamisole. In stillother embodiments, the long-acting compositions of the present inventionmay include tetrahydropyrimidine active agents including, but notlimited to, pyrantel, oxantel, and morantel. Suitable organophosphateactive agents include, but are not limited to, coumaphos, trichlorfon,haloxon, naftalofos and dichlorvos, heptenophos, mevinphos,monocrotophos, TEPP, and tetrachlorvinphos.

In other embodiments, the long-acting injectable compositions of thepresent invention may include the antinematodal compounds phenothiazineand piperazine as the neutral compound or in various salt forms,diethylcarbamazine, phenols such as disophenol, arsenicals such asarsenamide, ethanolamines such as bephenium, thenium closylate, andmethyluridine; cyanine dyes including pyrvinium chloride, pyrviniumpamoate and dithiazanine iodide; isothiocyanates including bitoscanate,suramin sodium, phthalofyne, and various natural products including, butnot limited to, hygromycin B, ca-santonin and kainic acid.

In other embodiments, the long-acting injectable compositions of thepresent invention of the invention may include anti-trematodal agents.Suitable anti-trematodal agents include, but are not limited to, themiracils such as miracil D and mirasan; praziquantel, clonazepam and its3-methyl derivative, oltipraz, lucanthone, hycanthone, oxamniquine,amoscanate, niridazole, nitroxynil, various bisphenol compounds known inthe art including hexachlorophene, bithionol, bithionol sulfoxide andmenichlopholan; various salicylanilide compounds includingtribromsalane, oxyclozanide, diloxanide, rafoxanide, brotianide,bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon,hetolin and emetine.

Anticestodal compounds may also be advantageously used in thelong-acting compositions of the present invention of the inventionincluding, but not limited to, arecoline in various salt forms,bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.

In yet other embodiments, the long-acting injectable compositions of thepresent invention may include other active agents that are effectiveagainst arthropod parasites. Suitable active agents include, but are notlimited to, bromocyclen, chlordane, DDT, endosulfan, lindane,methoxychlor, toxaphene, bromophos, bromophos-ethyl, carbophenothion,chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate, diazinon,dichlorenthion, diemthoate, dioxathion, ethion, famphur, fenitrothion,fenthion, fospirate, iodofenphos, malathion, naled, phosalone, phosmet,phoxim, propetamphos, ronnel, stirofos, allethrin, cyhalothrin,cypermethrin, deltamethrin, fenvalerate, flucythrinate, permethrin,phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon disulfide,crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornylthiocyanato acetate, methoprene, monosulfiram, pirenonylbutoxide,rotenone, triphenyltin acetate, triphenyltin hydroxide, deet, dimethylphthalate, and the compounds1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde (MGK-11),2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione(MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and2-(octylthio)ethanol (MGK-874).

An antiparasitic agent that can be combined with an isoxazolinecompounds in the long-acting compositions of the present invention canbe a biologically active peptide or protein including, but not limitedto, depsipeptides, which act at the neuromuscular junction bystimulating presynaptic receptors belonging to the secretin receptorfamily resulting in the paralysis and death of parasites. In oneembodiment of the depsipeptide, the depsipeptide is emodepside (seeWillson et al., Parasitology, Jan. 2003, 126(Pt 1):79-86). In anotherembodiment, the depsipeptide is PF1022A or a derivative thereof.

In another embodiment, the long-acting injectable compositions of thepresent invention may comprise an active agent from the neonicotinoidclass of pesticides. The neonicotinoids bind and inhibit insect specificnicotinic acetylcholine receptors. In one embodiment, the neonicotinoidinsecticidal agent that can be combined with an isoxazoline compound toform a long-acting injectable composition of the invention isimidacloprid. Imidacloprid is a well-known neonicotinoid active agentand is the key active ingredient in the topical parasiticide productsAdvantage®, Advantage® II, K9 Advantix®, and K9 Advantix® II sold byBayer Animal Health and the oral soft-chewable composition Advantus™from Piedmont Animal Health. Agents of this class are described, forexample, in U.S. Pat. No. 4,742,060 or in EP 0 892 060.

In another embodiment, the long-acting injectable compositions of thepresent invention may comprise nitenpyram, another active agent of theneonicotinoid class of pesticides. Nitenpyram has the following chemicalstructure and is the active ingredient in the oral product CAPSTAR™Tablets sold by Novartis Animal Health.

Nitenpyram is active against adult fleas when given daily as an oraltablet. Nitenpyram works by interfering with normal nerve transmissionand leads to the death of the insect. Nitenpyram has a very fast onsetof action against fleas. For example, CAPSTAR™ Tablets begin to actagainst fleas in as early as 30 minutes after administration and isindicated for use as often as once a day. However, nitenpyram is onlyknown to be effective when administered orally as a systemicparasiticide, as with CAPSTAR™ Tablets.

In yet another embodiment, the invention provides the long-actingcompositions of the present invention comprising4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide(Compound of formula Ia) in combination with nitenpyram.

In yet another embodiment, the invention provides the long-actingcompositions of the present invention comprising4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide(Compound of formula Ia) in combination with imidacloprid.

In certain embodiments, an insecticidal agent that can be combined withthe long-acting compositions of the present invention is asemicarbazone, such as metaflumizone.

In another embodiment, the long-acting injectable compositions of thepresent invention may advantageously include a combination ofisoxazoline compounds known in the art. These active agents aredescribed in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO2009/024541, WO 2005/085216 and US 2007/0066617 and WO 2008/122375, allof which are incorporated herein by reference in their entirety.

In another embodiment of the invention, nodulisporic acid and itsderivatives (a class of known acaricidal, anthelmintic, anti-parasiticand insecticidal agents) may be added to the long-acting compositions ofthe present invention. These compounds are used to treat or preventinfections in humans and animals and are described, for example, in U.S.Pat. Nos. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of whichare hereby incorporated by reference in their entirety. The compositionsmay include one or more of the known nodulisporic acid derivatives inthe art, including all stereoisomers, such as those described in thepatents cited above.

In another embodiment, anthelmintic compounds of the amino acetonitrileclass (AAD) of compounds such as monepantel (ZOLVIX), and the like, maybe added to the. the long-acting compositions of the present inventionThese compounds are described, for example, in WO 2004/024704 and U.S.Pat. No. 7,084,280 (incorporated by reference); Sager et al., VeterinaryParasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13Mar. 2008, 176-181.

The compositions of the invention may also include aryloazol-2-ylcyanoethylamino compounds such as those described in U.S. Pat. No.8,088,801 to Soll et al., which is incorporated herein in its entirety,and thioamide derivatives of these compounds, as described in U.S. Pat.No. 7,964,621, which is incorporated herein by reference.

The long-acting injectable compositions of the present invention mayalso be combined with paraherquamide compounds and derivatives of thesecompounds, including derquantel (see Ostlind et al., Research inVeterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical andVeterinary Entomology, 1997, 11, 407-408). The paraherquamide family ofcompounds is a known class of compounds that include a spirodioxepinoindole core with activity against certain parasites (see Tet. Lett.1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991,44, 492). In addition, the structurally related marcfortine family ofcompounds, such as marcfortines A-C, are also known and may be combinedwith the compositions of the invention (see J. Chem. Soc. —Chem. Comm.1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to theparaherquamide derivatives can be found, for example, in WO 91/09961, WO92/22555, WO 97/03988, WO 01/076370, WO 09/004432, U.S. Pat. Nos.5,703,078 and 5,750,695, all of which are hereby incorporated byreference in their entirety.

In general, the additional active agent is included in the long-actingcompositions of the present invention in an amount of between about 0.1μg and about 1000 mg. More typically, the additional active agent may beincluded in an amount of about 10 μg to about 500 mg, about 1 mg toabout 300 mg, about 10 mg to about 200 mg or about 10 mg to about 100mg.

In other embodiments of the invention, the additional active agent maybe included in the composition to deliver a dose of about 5 μg/kg toabout 50 mg/kg per weight of the animal. In other embodiments, theadditional active agent may be present in an amount sufficient todeliver a dose of about 0.01 mg/kg to about 30 mg/kg, about 0.1 mg/kg toabout 20 mg/kg, or about 0.1 mg/kg to about 10 mg/kg of weight ofanimal. In other embodiments, the additional active agent may be presentin a dose of about 5 μg/kg to about 200 μg/kg or about 0.1 mg/kg toabout 1 mg/kg of weight of animal. In still another embodiment of theinvention, the additional active agent is included in a dose betweenabout 0.5 mg/kg to about 50 mg/kg.

The long-acting compositions of the present invention, which include atleast an isoxazoline active agent, at least one liquid PEG and/or aneutral oil and optionally a co-solvent, have been surprisinglydiscovered to be stable and effective against a broad spectrum ofectoparasites, and possibly also endoparasites if another active isincluded, for an extended period of time; e.g., a period from three (3)to six (6) months while exhibiting favorable properties with respect tothe site of injection.

Liquid PEGs as provided for herein are those polyethylene glycols thatare liquid at room temperature (20-30° C.). Polyethylene glycols havethe following structural formula:H—(O—CH₂—CH₂)_(n)—OH.

Non-limiting examples for n in the above formula are those compoundswhen n is from 1 to about 10,000 (e.g., from about 4 to about 25).Liquid PEGs include combinations of different polyethylene glycols.Non-limiting examples of liquid PEGs include PEG 200, PEG 300, PEG 400,PEG 600, and PEG 1000 or combinations thereof.

Pharmaceutically acceptable polymers other than PEGs are specificallyexcluded from the inventive long-acting compositions. Examples ofpharmaceutically acceptable polymers that are specifically excluded fromthe inventive long-acting compositions include polylactides,polyglycolides, polycaprolactones, polyanhydrides, polyamides,polyurethanes, polyester amides, polyorthoesters, polydioxanones,polyacetals, polyketals, polycarbonates, polyorthocarbonates,polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates,polyalkylene oxalates, polyalkylene succinates, poly(malic acid),poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride),chitin, chitosan, and copolymers, terpolymers, or combinations ormixtures therein including copolymers of polylactides,polycaprolactones, polyglycolides (e.g., poly(lactide-co-glycolide).

In some embodiments, poloxamers may be included in the compositions. Forthe purpose of the compositions described herein, poloxamers are notconsidered pharmaceutically-acceptable polymers but solvents orsurfactants. Poloxamers are a family of synthetic block copolymers ofethylene oxide and propylene oxide. Poloxamers may be liquid, a milkywhite paste or a powder and are represented by the following structure:

where a is an integer between 2 and 130 and b is an integer between 15and 67 (see, U.S. Pat. No. 3,740,421, incorporated herein by reference).Poloxamer are available from commercial sources such as BASF and Croda.An example of a poloxamer that may be used in the compositions of theinvention is P-124 which is a solid at room temperature. The viscosityof the long-acting injectable compositions is an important parameterwith respect to the ability to easily administer the composition toanimals. Typically, viscosities of about less than 150 centipois (cPs)are acceptable. Thus, in one embodiment, the viscosity of thecompositions of the invention at 25° C. is about less than 150 cPs. Inother embodiments, the viscosity of the compositions of the inventionare 25° C. is about less than 140 cPs, less than about 130 cPs or lessthan about 120 cPs. In other embodiments, the viscosity of thecompositions of the invention at 25° C. is about less than 110 cPs orless than about 100 cPs.

The co-solvents used in the long-acting injectable compositions may be asingle or a blend of co-solvents. Co-solvents may be used in thecompositions of the invention to improve the solubility of theisoxazoline active agent and/or to lower the viscosity of thecompositions. In one embodiment, the co-solvents used in the long-actinginjectable compositions of the present invention include polar solventsthat are miscible in water. Non-limiting examples of these co-solventsinclude ethanol, isopropanol, glycol ethers (e.g., including, butlimited to, diethyleneglycol monoethyl ether (DGME, Transcutol®), butyldiglycol, dipropylene glycol n-butyl ether, ethyleneglycol monoethylether, ethyleneglycol monomethyl ether, dipropylene glycol monomethylether, propylene glycol monomethyl ether, propylene glycol monoethylether, and the like), propylene glycol, glycerin, carbonates (e.g.,propylene carbonate or ethylene carbonate), 2-pyrrolidone, substituted2-pyrrolidones including N-methylpyrrolidone, 1-ethylpyrrolidone,1-octylpyrrolidone, 1-dodecylpyrrolidone, 1-isopropylpyrrolidone,1-(sec- or t- or n-butyl)pyrrolidone, 1-hexylpyrrolidone,1-vinyl-2-pyrrolidone, 1-cyclohexylpyrrolidone,1-(2-hydroxyethyl)-pyrrolidone, 1-(3-hydroxypropyl)pyrrolidone,1-(2-methoxyethy 1)-pyrrolidone, 1-(3-methoxypropyl)pyrrolidone and1-benzylpyrrolidone; dimethyl isosorbide (DMI), dimethylacetamide (DMA),dimethylsulfoxide (DMSO), glycerol formal or a mixture of at least twoof these solvents.

In one embodiment, the long-acting compositions of the inventioncomprise a polar protic solvent including, but not limited to, analcohol such a C₁-C₆alcohol including, but not limited to, ethanol,isopropanol. In another embodiment, the polar protic solvent is aglycol, such as glycerol or propylene glycol, or a glycol ether such asdiethylene glycol monoethyl ether (Transcutol) or other commonly usedglycol ethers such as those described above.

In another embodiment, the long-acting injectable compositions of theinvention comprise a polar aprotic solvent including, but not limitedto, N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide,dimethylsulfoxide or propylene carbonate.

In yet another embodiment of the invention, the compositions of theinvention include non-water miscible co-solvents or solvents with onlypartial solubility in water. Non-water miscible solvents include estersof aliphatic carboxylic acids (including fatty acids) and glycerol(glycerides) or esters of aliphatic carboxylic acids (including fattyacids) and propylene glycol. Non-water miscible solvents also includeoils that are acceptable for injectable compositions. Non-limitingexamples of these co-solvents include benzyl alcohol, benzyl benzoate,ethyl acetate, triacetin, lipids, triglycerides including medium chaintriglycerides such C₈-C₁₀ triglycerides such as capric/caprilictriglycerides, propylene glycol derivatives (e.g. propylene glycolmonolaurate), caprylocaproyl polyoxyl-8 glycerides (Labrasol) (non-ionicwater dispersible surfactant, isopropyl myristate, or a mixture of atleast two of these co-solvents.

In one embodiment, the composition of the invention may includepharmaceutically acceptable neutral oils as a main component of thecomposition or as a co-solvent with the liquid PEG. When a neutral oilus used in combination with a liquid PEG, it may be necessary to use abridging solvent or a surfactant to ensure miscibility. Some neutraloils are triglycerides of fractionated plant fatty acids with chainlengths of C₈ to C₁₀, including caprylic/capric triglycerides. Twocommercially available products are known as MIGLYOL® 810 andMIGLYOL®812. In another embodiment, the neutral oil is a triglyceride offractionated plant fatty acids with chain lengths of C₈ and C₁₀ combinedwith linoleic acid (about 4-5%). A commercially available product isknown as MIGLYOL® 818. In yet another embodiment, the neutral oil is aglycerin ester of fractionated plant fatty acids with chain lengths ofC₈ and C₁₀ combined with succinic acid. A commercially available productis known as MIGLYOL® 829. In another embodiment, the neutral oil may bea propylene glycol diester of saturated plant fatty acids with chainlengths of C₈ and C₁₀. A commercially available product is known asMIGLYOL® 840 (propylene glycol dicaprylate/dicaprate). In yet anotherembodiment, the co-solvent may be a mixture of two or more neutral oils.Other oils that are acceptable to include in the long-acting injectablecompositions of the invention include, but are not limited to, castoroil, cottonseed oil, sesame oil, soybean oil and safflower oil.

In one embodiment, the compositions of the invention may comprise about0.5% to about 70% (w/v) of a co-solvent. In another embodiment, thecompositions of the invention may comprise about 0.5% to about 60% (w/v)or about 1 to about 50% (w/v) of a co-solvent. In still anotherembodiment, the compositions may comprise about 1% to about 40% (w/v),about 5% to about 50% (w/v), about 5% to about 40% (w/v) or about 5% toabout 35% (w/v) of a co-solvent. In other embodiments, the compositionsof the invention may comprise about 1% to about 20% (w/v), about 2% toabout 15% (w/v) or about 2% to about 10% (w/v) of the co-solvent.

The long-acting injectable compositions of the invention may includepharmaceutically acceptable additives or excipients. Pharmaceuticallyacceptable additives and excipients include, but are not limited to,surfactants, antioxidants, preservatives, pH stabilizing agents (e.g.buffers), and other non-active excipients. In another embodiment, thecompositions of the invention may comprise about 0.01% to about 20%(w/v) of a pharmaceutically acceptable additive, excipient or mixturesthereof. In other embodiments, the compositions may comprise about 0.01%to about 5% (w/v), about 0.1% to about 10% (w/v) or about 0.1% to about5% (w/v) of a pharmaceutically acceptable additive, excipient ormixtures thereof. In other embodiments the compositions may compriseabout 5 to about 15% (w/v) or about 5 to about 10% (w/v) of apharmaceutically acceptable additive, excipient or mixtures thereof. Inyet another embodiment, the compositions may comprise about 7 to about10% of a pharmaceutically acceptable additive, excipient or mixturesthereof.

Surfactants may be present in the inventive compositions atconcentrations of about 0.1% to about 10% (w/w), about 1% to about 10%(w/w) or about 5% to about 10% (w/w). More typically, surfactants may bepresent at concentrations of about 0.1% to about 5% (w/w) or about 1 toabout 5% (w/w). Examples of surfactants that may be used in thecompositions include, but are not limited to, glyceryl monooleate,polyoxyethylene sorbitan fatty acid esters, sorbitan esters includingsorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbatesincluding polysorbate 20 and polysorbate 80, d-α-tocopherol polyethyleneglycol 1000 succinate (TPGS), sodium lauryl sulfate, co-polymers ofethylene oxide and propylene oxide (e.g. poloxamers such as LUTROL® F87and the like), polyethylene glycol castor oil derivatives includingpolyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castoroil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor®RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride estersincluding glycerol caprylate/caprate (CAPMUL® MCM), polyglycolizedglycerides (GELUCIRE®), PEG 300 caprylic/capric glycerides (Softigen®767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleicglycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil®M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl40 stearate (PEG 1750 monostearate, and the like). Polyethylene glycolstearates (synonyms include macrogol stearates, polyoxylstearates,polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3,9005-08-7) are mixtures of mono- and distearate esters of mixedpolyoxyethylene polymers. Polyethylene glycol hydroxystearate is amixture of mono- and diesters of hydroxystearic acid with polyethyleneglycols. One polyethylene glycol hydroxystearate that may be used in thecompositions is polyethylene glycol 12-hydroxystearate. In anotherembodiment, the inventive compositions may include the surfactantpolyethylene glycol 15 12-hydroxystearate (Kolliphor® HS 15 from BASF),a mixture of mono- and diesters of 12-hydroxystearic acid with 15 molesof ethylene oxide. Again, these compounds, as well as their amounts arewell known in the art. In another embodiment of the invention, theinventive compositions may include polyoxyl 35 castor oil (Kolliphor®EL) as a surfactant. In other embodiments, the inventive compositionsmay include polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40) orpolyoxyl 60 hydrogenated castor oil as surfactants. The compositions ofthe invention may also include a combination of surfactants.

The inventive compositions may contain other inert ingredients such asantioxidants, preservatives, or pH stabilizers. These compounds are wellknown in the composition art. Antioxidants such as vitamin E, alphatocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaricacid, malic acid, sodium ascorbate, sodium metabisulfate, sodiummetabisulfite, n-propyl gallate, BHA (butylated hydroxy anisole), BHT(butylated hydroxy toluene), BHA and citric acid, monothioglycerol,tert-butyl hydroquinone (TBHQ), and the like, may be added to thepresent composition. The antioxidants are generally included in thecompositions of the invention in amounts of about 0.01% to about 3%, orfrom about 0.01 to about 2% (w/v), based upon total weight of thecomposition (w/w). In another embodiment, the compositions contain about0.05 to about 1.0% (w/w) of one or a mixture of antioxidants.

Preservatives, such as the parabens (methylparaben and/orpropylparaben), are suitably used in the composition in amounts rangingfrom about 0.01 to about 2.0%, with about 0.05 to about 1.0% beingespecially preferred. Other preservatives include benzalkonium chloride,benzethonium chloride, benzoic acid, benzyl alcohol, bronopol,butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol,cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol,phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate,phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodiumpropionate, sorbic acid, thimerosal, and the like. Preferred ranges forthese compounds include from about 0.01 to about 5%.

Compounds which stabilize the pH of the composition are alsocontemplated. Again, such compounds are well known to a practitioner inthe art as well as how to use these compounds. Buffering systemsinclude, for example, systems selected from the group consisting ofacetic acid/acetate, malic acid/malate, citric acid/citrate, tartaricacid/tartrate, lactic acid/lactate, phosphoric acid/phosphate,glycine/glycimate, tris, glutamic acid/glutamates and sodium carbonate.

Dosage forms may contain from about 0.5 mg to about 5 g of an activeagent or a combination of active agents. More typically, the amount ofactive agent(s) in the compositions of the invention will be from about1 mg to about 3 g. In another embodiment, the amount of active agent(s)in the compositions will be from about 20 mg to about 3 g. In anotherembodiment, the amount of active agent(s) present in the compositionswill be from about 20 mg to about 2 g, about 20 mg to about 1.5 g orabout 20 mg to about 1 g. In other embodiments, the amount of activeagent(s) in the compositions will be from about 20 mg to about 500 mg,about 30 mg to about 200 mg or about 50 mg to about 200 mg. In stillanother embodiment, the amount of active agent(s) present in thecompositions will be from about 50 mg to about 2 g, about 50 mg to about1 g or about 50 mg to about 500 mg. In yet another embodiment of theinvention, the about of active agent(s) present will be from about 100mg to about 2 g, about 100 mg to about 1 g or about 100 mg to about 500mg.

In another embodiment, the amount of active agent(s) present in thecompositions of the invention is from about 1 mg to about 500 mg of anactive agent, about 1 mg to about 100 mg or about 1 mg to about 25 mg.In still other embodiments, the amount of the active agent present inthe compositions is about 10 mg about 50 mg or about 10 mg to about 100mg. In other embodiments, the amount of active agent present in thecompositions is about 50 mg to about 200 mg, about 100 mg to about 300mg, about 100 mg to about 400 mg, about 200 mg to about 500 mg, about300 mg to about 600 mg, about 400 mg to about 800 mg, or about 500 mg toabout 1000 mg.

The compositions of the invention are made by mixing the appropriateamount of the active agents, a liquid PEG and/or a neutral oil, aco-solvent (if present) and, optionally, an antioxidant,pharmaceutically acceptable additive and/or excipient to form acomposition of the invention. In some embodiments the compositions ofthe present invention can be obtained by following the method of makingthese forms described above by the description of making these formsfound in general composition text known to those in the art, e.g.Remington—The Science and Practice of Pharmacy (21^(st) Edition) (2005),Goodman & Gilman's The Pharmacological Basis of Therapeutics (11^(th)Edition) (2005) and Ansel's Pharmaceutical Dosage Forms and DrugDelivery Systems (8^(th) Edition), edited by Allen et al., LippincottWilliams & Wilkins, (2005).

Methods of Treatment

In another aspect of the invention, a method for preventing or treatinga parasite infestation/infection in an animal is provided, comprisingadministering to the animal a long-acting injectable compositioncomprising an effective amount of at least one isoxazoline compound, aliquid PEG and/or a neutral oil, optionally a co-solvent, andoptionally, an antioxidant, pharmaceutically acceptable additive and/orexcipient. The compositions of the invention have long-lasting efficacyagainst ectoparasites (e.g. fleas and ticks) and in certain embodimentsmay also be active against endoparasites that harm animals.

In one embodiment of the invention, methods for the treatment orprevention of a parasitic infestation or infection in a livestock animalare provided, which comprise administering a long-acting injectablecomposition comprising an effective amount of at least one isoxazolineactive agent to the animal. Ectoparasites against which the methods andcompositions of the invention are effective include, but are not limitedto, fleas, ticks, mites, mosquitoes, flies and lice. In certainembodiments wherein the inventive compositions include one or moreadditional active agents that are active against internal parasites thecompositions and methods of the invention may also be effective againstendoparasites including, but not limited to, cestodes, nematodes,hookworms and roundworms of the digestive tract of animals and humans.

In an alternative embodiment of the invention, methods for the treatmentor prevention of a parasitic infestation or infection in a domesticanimal are provided, which comprise administering a long-actinginjectable composition comprising an effective amount of at least oneisoxazoline active agent to the animal. Ectoparasites against which themethods and compositions of the invention are effective include, but arenot limited to, fleas, ticks, mites, mosquitoes, flies and lice. Incertain embodiments wherein the inventive compositions include one ormore additional active agents that are active against internal parasitesthe compositions and methods of the invention may also be effectiveagainst endoparasites including, but not limited to, cestodes,nematodes, hookworms and roundworms of the digestive tract of animalsand humans.

In one embodiment for treatment against ectoparasites, the ectoparasiteis one or more insect or arachnid including those of the generaCtenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus,Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes,Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes,Trichodectes, and Felicola.

In another embodiment for the treatment against ectoparasites, theectoparasite is from the genera Ctenocephalides, Rhipicephalus,Dermacentor, Ixodes and/or Boophilus. The ectoparasites treated includebut are not limited to fleas, ticks, mites, mosquitoes, flies, lice,blowfly and combinations thereof. Specific examples include, but are notlimited to, cat and dog fleas (Ctenocephalides felis, Ctenocephalidessp. and the like), ticks (Rhipicephalus sp., Ixodes sp., Dermacentorsp., Amblyomma sp. and the like), and mites (Demodex sp., Sarcoptes sp.,Otodectes sp. and the like), lice (Trichodectes sp., Cheyletiella sp.,Linognathus sp., and the like), mosquitoes (Aedes sp., Culex sp.,Anopheles sp., and the like) and flies (Haematobia sp. includingHaematobia irritans, Musca sp., Stomoxys sp. including Stomoxyscalcitrans, Dermatobia sp., Cochliomyia sp., and the like).

Additional examples of ectoparasites include but are not limited to thetick genus Boophilus, especially those of the species microplus (cattletick), decoloratus and annulatus; myiasis such as Dermatobia hominis(known as Berne in Brazil) and Cochliomyia hominivorax (greenbottle);sheep myiasis such as Lucilia sericata, Lucilia cuprina (known asblowfly strike in Australia, New Zealand and South Africa). Fliesproper, namely those whose adult constitutes the parasite, such asHaematobia irritans (horn fly) and Stomoxys calcitrans (stable fly);lice such as Linognathus vituli, etc.; and mites such as Sarcoptesscabiei and Psoroptes ovis. The above list is not exhaustive and otherectoparasites are well known in the art to be harmful to animals andhumans. These include, for example migrating dipterous larvae.

In some embodiments of the invention, the composition can also be usedto treat against endoparasites such as those helminths selected from thegroup consisting of Anaplocephala, Ancylostoma, Necator, Ascaris,Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius,Fasciola, Haemonchus, Oesophagostomum, Ostertagia, Toxocara,Strongyloides, Toxascaris, Trichinella, Trichuris, and Trichostrongylus,among others.

In one embodiment, the invention provides methods for the treatment andprevention of parasitic infections and infestations in or on animals(either wild or domesticated), including livestock and companion animalssuch as cats, dogs, horses, birds including chickens, sheep, goats,pigs, deer, turkeys and cattle, with the aim of ridding these hosts ofparasites commonly encountered by such animals.

In an embodiment, the invention provides methods and compositions forthe treatment or prevention of parasitic infections and infestations inlivestock animals (e.g., sheep and cattle) or companion animalsincluding, but not limited to, cats and dogs. The methods andcompositions are particularly effective for preventing or treatingparasitic infestations of cattle and sheep with fleas and ticks.

In another embodiment, the methods and compositions of the invention areused for the treatment or prevention of parasitic infections andinfestations in cattle or sheep. When treating livestock animals such ascattle or sheep, the methods and compositions are particularly effectiveagainst Rhipicephalus (Boophilus) microplus, Haematobia irritans (hornfly), Stomoxys calcitrans (stable fly), and sheep myiasis such asLucilia sericata, Lucilia cuprina (known as blowfly strike in Australia,New Zealand and South Africa).

The terms “treating” or “treat” or “treatment” are intended to mean theadministration of a long-acting composition of the present invention toan animal that has a parasitic infestation for the eradication of theparasite or the reduction of the number of the parasites infesting theanimal undergoing treatment. It is noted that the compositions of theinvention may be used to prevent such a parasitic infestation.

The terms “prevent”, “prevention” or “prophylaxis” are intended to meanthe administration of the long-acting compositions of the presentinvention to the animal before the parasitic infection or infestationhas occurred in order to keep said infection or infestation fromoccurring. Administration of the long-acting compositions at recommendedregular intervals effectively prevents new parasitic infestations orinfections in animals by killing new parasites that attack an animalbefore they can multiply to establish an infestation or infection.

The compositions of the invention are administered in parasiticidallyeffective amounts which are which are suitable to control the parasitein question to the desired extent, as described below. In each aspect ofthe invention, the compounds and compositions of the invention can beapplied against a single pest or combinations thereof.

By “antiparasitic effective amount” is intended a sufficient amount of acomposition of the invention to eradicate or reduce the number ofparasites infesting the animal. In some embodiments, an effective amountof the active agent achieves at least 70% efficacy against the targetparasite. In other embodiments, an effective amount of the active agentachieves at least 80%, or at least 90% efficacy against the targetpests. Preferably, an effective amount of the active agent will achieveat least 95%, at least 98% or 100% efficacy against the targetparasites.

Generally, a dose of from about 0.001 to about 100 mg per kg of bodyweight given as a single dose or in divided doses for a period of from 1to 5 days will be satisfactory but, of course, there can be instanceswhere higher or lower dosage ranges are indicated, and such are withinthe scope of this invention. It is well within the routine skill of thepractitioner to determine a particular dosing regimen for a specifichost and parasite.

In some embodiments for companion animals, the dose of the isoxazolineactive agent administered from the topical compositions of the inventionis between about 0.1 to about 50 mg per kg of body weight. Moretypically the dose of the isoxazoline active agent administered is about0.5 to about 30 mg/kg or about 0.5 to about 30 mg/kg body weight. In yetanother embodiment, the dose of the isoxazoline active agent will befrom about 0.5 to about 20 mg/kg, about 0.5 to about 10 mg/kg or about0.5 to about 5 mg/kg body weight. In another embodiment, the dose willbe from about 0.5 to about 2.5 mg/kg body weight. In another embodiment,the dose of the isoxazoline active agent administered is about 10 toabout 30 mg/kg, about 15 to about 30 mg/kg or about 20 to about 30 mg/kgof body weight.

In other embodiments, the dose administered may be lower depending onthe animal and the isoxazoline administered. For example, if thecomposition comprises the more active enantiomer of the isoxazolinecompounds a lower dose may be administered. In some embodiments, thedose is from about 0.1 to about 30 mg/kg of body weight. In anotherembodiment, the dose may be from about 0.1 to about 20 mg/kg or about0.1 to about 10 mg/kg of body weight. In another embodiment, a dose offrom about 0.1 to about 5 mg/kg, from about 0.1 to about 2.5 mg/kg bodyweight will be used. In other embodiments, the dose may be from about 1to about 20 mg/kg of body weight or about 1 to about 10 mg/kg. In yetanother embodiment, the dose may be from about 5 to about 20 mg/kg orabout 10 to about 20 mg/kg of body weight.

The volume of the dose of the long-acting injectable compositions istypically less than about 10 mL/50 kg body weight of the animal beingtreated. In other embodiments, the injection volume is about 7 mL/50 kgbody weight. In yet other embodiments, the injection volume is less thanabout 5 mL/50 kg, less than about 3 mL/50 kg body weight or less thanabout 2 mL/50 kg of body weight. In yet other embodiments, the injectionvolume is from about 0.1 to about 2 mL/50 kg body weight of the animal.In other embodiments, the injection volume is about 0.05 to about 1mL/50 kg body weight of the animal.

In other embodiments for the treatment of livestock animals such ascattle or sheep, doses of the isoxazoline active agent administered maybe about 0.1 to about 40 mg/kg of body weight. More typically the dosesadministered will be about 1 to about 30 mg/kg, about 1 to about 20mg/kg or about 1 to about 10 mg/kg of bodyweight. In yet anotherembodiment, the dose may be from about 10 to about 25 mg/kg, about 15 toabout 30 mg/kg of body weight or about 20-30 mg/kg of body weight.

In one embodiment of the method of use in livestock animals (e.g.,cattle or sheep), the long-acting compositions of the present inventioncomprising an isoxazoline compound has an efficacy against ectoparasitesincluding, but not limited to, fleas, ticks, mites, and parasitic flies,of at least about 90.0% or higher for about 3 months, or longer. Inanother embodiment, the long-acting compositions of the presentinvention provide an efficacy against ectoparasites of at least 95.0% orhigher for about 3 months or longer.

In another embodiment, the long-acting compositions of the presentinvention provide an efficacy against ectoparasites in livestock animals(e.g., cattle or sheep) of at least about 80% for two months, or longer.In another embodiment, the long-acting compositions of the presentinvention efficacy against ectoparasites in livestock animals (e.g.,cattle or sheep) of about 90% for at least about 2 months. In stillanother embodiment, the compositions provide an efficacy of about 95%for about 2 months or longer. In another embodiment, the long-actingcompositions of the present invention efficacy against ectoparasites inlivestock animals (e.g., cattle or sheep) of about 90% for about 3months, or longer. In still another embodiment, the compositions providean efficacy of about 95% for about 3 months or longer.

In another embodiment, the long-acting compositions of the presentinvention have an efficacy of at least about 80% against ectoparasitesfor about 3 months, or longer. In still another embodiment, thelong-acting compositions of the invention provide an efficacy of atleast about 90% against ectoparasites for 3 months or longer. In yetanother embodiment, the long-acting compositions of the presentinvention of the invention provide an efficacy of at least about 95%against ectoparasites for 3 months or longer. In still anotherembodiment, the long-acting compositions of the present inventionprovide an efficacy against ectoparasites in livestock animals (e.g.,cattle or sheep) of at least 80% or at least 90% for about 3 months toabout 6 months or longer.

In other embodiments, the long-acting compositions of the invention havean efficacy of at least about 90% against ectoparasites including, butnot limited to, fleas, ticks, mites and parasitic flies, of about 7months or longer, about 8 months or longer or about 9 months or longer.In other embodiments, the long-acting compositions of the invention havean efficacy of at least about 90% against ectoparasites including, butnot limited to, fleas, ticks, mites and parasitic flies, of about 10months or longer, about 118 months or longer or even about 12 months orlonger.

In another aspect of the invention, a kit for the treatment orprevention of a parasitic infestation in an animal is provided, whichcomprises a long-acting composition of the invention and a syringe.

Antiparasitic Compounds

In a second aspect of the invention, novel and inventive pesticidal andparasiticidal isoxazoline compounds of formula (Id) are provided:

wherein X¹ is bromo, chloro, iodo or fluoro; and X² is chloro, fluoro orCF₃;

Y is a group Y-1, Y-2, Y-3, Y-4 where Z is N or CH, Y-5 or Y-6

Q is OH, —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃, —C(O)NHCH₂CH₂SCH₃ or(—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃.

The second aspect of the present invention includes at least thefollowing features:

(a) In one embodiment, the invention provides novel compounds of formula(Id), or pharmaceutically or agriculturally acceptable salts thereof,which are active against arthropod pests and parasites that harm animalsand plants;

(b) veterinary and pesticidal compositions for combating and controllingpests and parasites comprising a pesticidally or parasiticidallyeffective amount of the compounds of formula (Id), or pharmaceuticallyor agriculturally acceptable salts thereof, in combination with apharmaceutically or agriculturally acceptable carrier or diluent;

(c) plant propagation material (e.g. seed), comprising at least onecompound of formula (Id), or agriculturally acceptable salts thereof.

(d) veterinary and pesticidal compositions for combating arthropod pestsand parasites comprising a pesticidally or parasiticidally effectiveamount of the compounds of the invention, or pharmaceutically oragriculturally acceptable salts thereof, in combination with at leastone additional active agent and a pharmaceutically or agriculturallyacceptable carrier or diluent;

(e) methods for treating a parasitic infestation/infection in or on ananimal are provided, which methods comprise administering aparasiticidally effective amount of a compound of formula (Id), orpharmaceutically acceptable salts thereof, to the animal in needthereof;

(f) methods for the prevention of a parasitic infestation/infection ofan animal, which comprise administering a parasiticidally effectiveamount of a compound of formula (Id), or pharmaceutically acceptablesalts thereof, to the animal in need thereof;

(g) methods for combating or controlling pests that are detrimental tocrops, plants, plant propagation material, or material containing woodor derived from wood, comprising contacting the crop, plants, plantpropagation material, or material containing wood or derived from wood,with a pesticidally effective amount of a compound of formula (Id), oran agriculturally acceptable salt thereof, or a composition comprisingthe compounds;

(h) methods for combating or controlling pests at a locus, comprisingadministering a pesticidally or parasiticidally effective amount of acompound of formula (Id), or pharmaceutically or agriculturallyacceptable salts thereof, to the locus;

(i) use of the compounds of formula (Id), or pharmaceutically oragriculturally acceptable salts thereof, for controlling pests,including parasites, in or on an animal or on crops, plants, plantpropagation material, or material containing wood or derived from wood;and

(j) use of the compounds of formula (Id), or pharmaceutically acceptablesalts thereof, in the manufacture of a veterinary medicament forcontrolling pests, including parasites.

An important aspect of the invention is to provide isoxazoline activeagents that exhibit surprising and unexpected fast-acting andlong-lasting efficacy against parasites, particularly ticks, thanisoxazoline active compounds having different substitution patterns onthe phenyl ring bound to the quaternary carbon of the isoxazoline ring.Thus, it has been found that the compound of formula (Id) in which Y isY-2, Q is —C(O)NHCH₂C(O)NHCH₂CF₃, X¹ is fluoro and X² is chloro, whichis not specifically described in WO 2007/079162 A1 or WO 2009/002890 A2,has been found to have surprisingly improved duration of activityagainst the tick Rhipicephalus microplus (formerly Boophilus microplus)on cattle compared with known isoxazoline compounds in which Y is Y-2and Q is —C(O)NHCH₂C(O)NHCH₂CF₃ but having different substitutionpatterns on the phenyl ring.

Furthermore, the compound of formula (Id) in which Y is Y-2, Q is—C(O)NHCH₂C(O)NHCH₂CF₃, X¹ is fluoro and X² is chloro, has also beenfound to have surprisingly improved fast-acting efficacy against thetick Rhipicephalus microplus on cattle compared with known isoxazolinecompounds in which Y is Y-2 and Q is Y is Y-2, Q is—C(O)NHCH₂C(O)NHCH₂CF₃ but having different substitution patterns on thephenyl ring.

In one embodiment, the invention provides a compound of formula (Id)wherein the group Y is Y-1. In another embodiment Y is Y-2. In anotherembodiment, Y is Y-3. In another embodiment, Y is Y-4. In still anotherembodiment, Y is Y-5. In another embodiment, Y is Y-6.

In one embodiment, the invention provides a compound of formula (Id)wherein Y is Y-1, X¹ is fluoro, and Q is —C(O)NHCH₂C(O)NHCH₂CF₃,—C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. In another embodiment, Y is Y-2,X¹ is fluoro, and Q is —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or—C(O)NHCH₂CH₂SCH₃. In another embodiment, Y is Y-3, X¹ is fluoro, and Qis (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminal CH₂ is bonded tothe benzylic carbon of Y-3. In another embodiment, Y is Y-4, X¹ isfluoro, and Q is —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or—C(O)NHCH₂CH₂SCH₃. In another embodiment, Y is Y-5, X¹ is fluoro, and Qis —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. In yetanother embodiment, Y is Y-6, X¹ is fluoro, and Q is OH.

In another embodiment, the invention provides a compound of formula (Id)wherein Y is Y-1, X¹ is chloro, and Q is —C(O)NHCH₂C(O)NHCH₂CF₃,—C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. In another embodiment, Y is Y-2,X¹ is chloro, and Q is —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or—C(O)NHCH₂CH₂SCH₃. In another embodiment, Y is Y-3, X¹ is chloro, and Qis (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminal CH₂ is bonded tothe benzylic carbon of Y-3. In another embodiment, Y is Y-4, X¹ ischloro, and Q is —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or—C(O)NHCH₂CH₂SCH₃. In another embodiment, Y is Y-5, X¹ is chloro, and Qis —C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. In yetanother embodiment, Y is Y-6, X¹ is chloro, and Q is OH.

In one embodiment, Y is Y-1, X¹ is fluoro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is fluoro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is fluoro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In another embodiment, Y is Y-1, X¹ is chloro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is chloro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is chloro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-1, X¹ is bromo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is bromo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is bromo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-1, X¹ is iodo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is iodo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-1, X¹ is iodo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-2, X¹ is fluoro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is fluoro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is fluoro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In another embodiment, Y is Y-2, X¹ is chloro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is chloro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is chloro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-2, X¹ is bromo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is bromo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is bromo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-2, X¹ is iodo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is iodo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-2, X¹ is iodo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-3, X¹ is fluoro, X² is chloro and Q is(—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminal CH₂ is bonded to thebenzylic carbon of Y-3. In another embodiment, Y is Y-3, X¹ is fluoro,X² is fluoro and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminalCH₂ is bonded to the benzylic carbon of Y-3. In another embodiment, Y isY-3, X¹ is fluoro, X² is CF₃ and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃where each terminal CH₂ is bonded to the benzylic carbon of Y-3.

In another embodiment, Y is Y-3, X¹ is chloro, X² is chloro and Q is(—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminal CH₂ is bonded to thebenzylic carbon of Y-3. In another embodiment, Y is Y-3, X¹ is chloro,X² is fluoro and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminalCH₂ is bonded to the benzylic carbon of Y-3. In another embodiment, Y isY-3, X¹ is chloro, X² is CF₃ and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃where each terminal CH₂ is bonded to the benzylic carbon of Y-3.

In one embodiment, Y is Y-3, X¹ is bromo, X² is chloro and Q is(—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminal CH₂ is bonded to thebenzylic carbon of Y-3. In another embodiment, Y is Y-3, X¹ is bromo, X²is fluoro and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminalCH₂ is bonded to the benzylic carbon of Y-3. In another embodiment, Y isY-3, X¹ is bromo, X² is CF₃ and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃where each terminal CH₂ is bonded to the benzylic carbon of Y-3.

In one embodiment, Y is Y-3, X¹ is iodo, X² is chloro and Q is(—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminal CH₂ is bonded to thebenzylic carbon of Y-3. In another embodiment, Y is Y-3, X¹ is iodo, X²is fluoro and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminalCH₂ is bonded to the benzylic carbon of Y-3. In another embodiment, Y isY-3, X¹ is iodo, X² is CF₃ and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ whereeach terminal CH₂ is bonded to the benzylic carbon of Y-3.

In one embodiment, Y is Y-4, X¹ is fluoro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is fluoro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is fluoro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In another embodiment, Y is Y-4, X¹ is chloro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is chloro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is chloro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-4, X¹ is bromo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is bromo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is bromo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-4, X¹ is iodo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is iodo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-4, X¹ is iodo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-5, X¹ is fluoro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is fluoro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is fluoro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In another embodiment, Y is Y-5, X¹ is chloro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is chloro, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is chloro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-5, X¹ is bromo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is bromo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is bromo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-5, X¹ is iodo, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is iodo, X² is fluoro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Y is Y-5, X¹ is iodo, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃, —C(O)CH₂S(O)₂CH₃ or —C(O)NHCH₂CH₂SCH₃.

In one embodiment, Y is Y-6, X¹ is fluoro, X² is chloro and Q is OH. Inanother embodiment, Y is Y-6, X¹ is fluoro, X² is fluoro and Q is OH. Inanother embodiment, Y is Y-6, X¹ is fluoro, X² is CF₃ and Q is OH.

In another embodiment, Y is Y-6, X¹ is chloro, X² is chloro and Q is OH.In another embodiment, Y is Y-6, X¹ is chloro, X² is fluoro and Q is OH.In another embodiment, Y is Y-6, X¹ is chloro, X² is CF₃ and Q is OH.

In one embodiment, Y is Y-6, X¹ is bromo, X² is chloro and Q is OH. Inanother embodiment, Y is Y-6, X¹ is bromo, X² is fluoro and Q is OH. Inanother embodiment, Y is Y-6, X¹ is bromo, X² is CF₃ and Q is OH.

In one embodiment, Y is Y-6, X¹ is iodo, X² is chloro and Q is OH. Inanother embodiment, Y is Y-6, X¹ is iodo, X² is fluoro and Q is OH. Inanother embodiment, Y is Y-6, X¹ is iodo, X² is CF₃ and Q is OH.

In another embodiment, Y is Y-1, X¹ is fluoro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Y is Y-1, X¹ is chloro,X² is fluoro and Q is —C(O)NHCH₂C(O)NHCH₂CF₃.

In one embodiment, Y is Y-2, X¹ is fluoro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Y is Y-1, X¹ is chloro,X² is chloro and Q is —C(O)NHCH₂C(O)NHCH₂CF₃.

In one embodiment, Y is Y-3, X¹ is fluoro, X² is chloro and Q is(—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminal CH₂ is bonded to thebenzylic carbon of Y-3. In another embodiment, Y is Y-3, X¹ is fluoro,X² is CF₃ and Q is (—CH₂—)(—CH₂—)N(CO)CH₂S(O)₂CH₃ where each terminalCH₂ is bonded to the benzylic carbon of Y-3.

In one embodiment, Y is Y-4 where Z is CH, X¹ is fluoro, X² is chloroand Q is —C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Y is Y-4 where Zis CH, X¹ is fluoro, X² is fluoro and Q is —C(O)NHCH₂C(O)NHCH₂CF₃. Inyet another embodiment, Y is Y-4, X¹ is fluoro, X² is CF₃ and Q is—C(O)NHCH₂C(O)NHCH₂CF₃.

In another embodiment, Y is Y-4, X¹ is chloro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Y is Y-4, X¹ is chloro,X² is fluoro and Q is —C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Yis Y-4, X¹ is chloro, X² is CF₃ and Q is —C(O)NHCH₂C(O)NHCH₂CF₃.

In one embodiment, Y is Y-5, X¹ is fluoro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Y is Y-5, X¹ is fluoro,X² is fluoro and Q is —C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Yis Y-5, X¹ is fluoro, X² is CF₃ and Q is —C(O)NHCH₂C(O)NHCH₂CF₃.

In another embodiment, Y is Y-5, X¹ is chloro, X² is chloro and Q is—C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Y is Y-5, X¹ is chloro,X² is fluoro and Q is —C(O)NHCH₂C(O)NHCH₂CF₃. In another embodiment, Yis Y-5, X¹ is chloro, X² is CF₃ and Q is —C(O)NHCH₂C(O)NHCH₂CF₃.

In a preferred embodiment, the invention provides a compound of formula(Ie) shown below, or a pharmaceutically or pharmaceutically acceptablesalt thereof:

As noted above, the isoxazoline compounds of formula (Id) can exist asstereoisomers since there is a chiral center in the molecule. Theindividual stereoisomers are encompassed by the structural formulasdepicted herein. The various stereoisomers include enantiomers,diastereomers and atropisomers.

Hence, in another embodiment, the invention provides isoxazolinecompounds of formula (Id), and compositions comprising the compounds,which are enriched in one enantiomer, or a pharmaceutically oragriculturally acceptable salt thereof.

In another embodiment, the invention provides isoxazoline compounds offormula (Id), and compositions comprising the compounds, which areenriched an enantiomer that displays significant in vitro and in vivoactivity with a favorable toxicity profile (the eutomer), or apharmaceutically acceptable salt thereof.

In one embodiment of the invention, the more biologically activeenantiomer of the compound of formula (Id) is believed to be compound offormula (S)-Id shown below. Accordingly, the more biologically activeenantiomers of isoxazoline compounds of formulae (Id) wherein Y is Y-1,Y-2, Y-3, Y-4, Y-5 and Y-6 have the (S) configuration at the chiralcarbon of the isoxazoline ring.

In an embodiment, the compounds of formulae formula (Id) (including(Ie)), or compositions comprising the compounds, are enriched in oneenantiomer over the other enantiomer in a weight:weight ratio of atleast 1.5:1. In another embodiment, the compounds of formula (Id) andcompositions comprising the compounds are enriched in one enantiomer ina weight:weight ratio of at least 2:1, at least 5:1, at least 10:1 or atleast 20:1.

In another embodiment, the compounds of formula (Id), or compositionscomprising the compounds, are essentially pure enantiomers. In oneembodiment, the compounds and composition of the invention comprises acompound of formula (Id) that is substantially enriched in anenantiomer. The term “substantially enriched” is meant wherein theweight:weight ratio is at least about 1.5:1 or higher in favor of thedesired enantiomer. In another embodiment, the compounds andcompositions of the invention are substantially enriched in the(S)-enantiomer. In another embodiment, the compounds and compositions ofthe invention are substantially enriched in the (R)-enantiomer.

In another embodiment of the invention, the compounds of formula (Id),or compositions comprising the compounds, are enriched in the(S)-enantiomer in a weight:weight ratio of at least about 2:1, (S) to(R), or greater. In yet another embodiment, the compounds orcompositions of the invention comprise a compound of formula (Id) thatis enriched in the (S)-enantiomer in a weight:weight ratio of at leastabout 5:1, (S) to (R), or greater. In still another embodiment, thecompounds and compositions of the invention comprise a compound offormula (Id), that is enriched in the (S)-enantiomer in a weight:weightratio of at least about 10:1, (S) to (R), or greater. In anotherembodiment, the compounds and compositions of the invention comprise acompound of formula (Id), that is enriched in the (S)-enantiomer in aweight:weight ratio of at least about 20:1, (S) to (R), or greater. Instill another embodiment, the compounds and compositions of theinvention comprise a compound of formula (Id), that is essentially thepure (S)-enantiomer.

In one embodiment, the invention provides a compound of formula (S)-Ie,or a pharmaceutically or pharmaceutically acceptable salt thereof, shownbelow:

In another embodiment, the invention provides a compound of formula(R)-Ie, or a pharmaceutically or pharmaceutically acceptable saltthereof, shown below:

In another embodiment, the invention provides pesticidal andparasiticidal compositions comprising a compound of formula (S)-Ie. Inyet another embodiment, the invention provides pesticidal andparasiticidal compositions comprising a compound of formula (R)-Ie. Forthe avoidance of doubt, the compositions of the invention comprising acompound of formula (S)-Ie or (R)-Ie may be enriched in the desiredenantiomer at the rations discussed above for the compound of formula(Id).

Processes for the Preparation of the Compounds of Formula (Id)

The compounds of formula (Id) and intermediates used in the processes tomake the compounds may be prepared by processes adapted from thosedescribed in U.S. Pat. Nos. 7,964,204, 8,410,153, 8,546,618, 8,217,180,8,546,613, 7,662,972, 8,466,115, 8,383,659, 8,853,186, 8,618,126, US2014/0371464, US 2015/0291612 and WO 2014/090918, all of which areincorporated herein by reference in their entirety.

In one embodiment, the compounds of the invention may be preparedaccording to the general process shown in Scheme 1 below, wherein Y, Q,X¹ and X² are as defined for formula (Id) above, W is Cl, Br or I and Ris alkyl.

This general process is described, for example, in U.S. Pat. No.8,546,618 to prepare compounds in which Y is Y-2. Using suitablysubstituted compounds of formula Id-1 and Id-4, a variety of compoundsof formula (Id) may be prepared. Processes for the preparationintermediates of formula Id-1, Id-3, Id-4 and Id-5 are described in U.S.Pat. Nos. 8,546,618 and 8,217,180, both incorporated herein byreference. The formation of isoxazoline compounds of formula (Id) fromId-5 is also described in U.S. Pat. Nos. 8,546,618 and 8,217,180.Additional information on processes for the preparation of intermediatesId-1, Id-3, Id-4 and Id-5 that may be used for the preparation ofcompounds of formula (Id) is found in U.S. Pat. Nos. 7,662,972,8,466,115, 8,383,659, 8,853,186, US 2014/0371464, US 2015/0291612 and WO2014/090918, all incorporated herein by reference in their entirety.

Animal Health Applications

I. Veterinary Compositions:

The compounds of formula (Id) and compositions comprising the compoundsare useful for the prevention and treatment of parasiticinfestations/infections in animals. The compositions of the inventioncomprise an effective amount of at least one isoxazoline compound offormula (Id), or a pharmaceutically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier or diluent andoptionally other non-active excipients. In a preferred embodiment, thecompositions of the invention comprise an effective amount of anisoxazoline of formula (Ie) or (S)-Ie, or a pharmaceutically acceptablesalt thereof. The compositions may be in a variety of solid and liquidforms which are suitable for various forms of application oradministration to an animal. For example, the veterinary compositionscomprising the inventive compounds may be in compositions suitable fororal administration, injectable administration, including subcutaneousand parenteral administration, and topical administration (e.g. spot-onor pour-on). The compositions are intended to be administered to ananimal including, but not limited to, mammals, birds and fish. Examplesof mammals include but are not limited to humans, cattle, sheep, goats,llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestockor domestic mammals. Examples of birds include turkeys, chickens,ostriches and other livestock or domestic birds. The use of thecompounds of formula (Id) to protect companion animals, such as dogs andcats, and livestock animals, such as cattle and sheep, fromectoparasites is particularly useful.

As discussed above, the compositions of the invention may be in a formsuitable for oral use (see, e.g., U.S. Pat. No. 4,564,631, which ishereby incorporated by reference in its entirety), dietary supplements,troches, lozenges, chewables, tablets, hard or soft capsules, bolus,emulsions, aqueous or oily suspensions, aqueous or oily solutions, oraldrench compositions, dispersible powders or granules, premixes, syrupsor elixirs, enteric compositions or pastes. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more sweetening agents, bittering agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 (all incorporated herein by reference in theirentirety) to form osmotic therapeutic tablets for controlled release.

Oral compositions include hard gelatin capsules, wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin. Capsules may also be softgelatin capsules, wherein the active ingredient is mixed with water ormiscible solvents such as propylene glycol, PEGs and ethanol, or an oilmedium, for example peanut oil, liquid paraffin, or olive oil.

In one embodiment, the compounds of formula (Id) may be administered inchewable tablet compositions or soft chewable compositions such as thosedescribed in U.S. Pat. No. 9,233,100 B2, U.S. Pat. No. 9,259,417, US2010/0087492, US 2006/0222684, US 2004/0151759, U.S. Pat. No. 7,955,632,US 2015/0057321, US 2015/0057239 and WO 2016/073347, all incorporatedherein by reference in their entirety.

The veterinary compositions may be in the form of a soft chewablecomposition (“soft chew”) which is palatable and acceptable to theanimal. In addition to the active ingredient(S), the soft chews of theinvention may include one or more of the following components: a solventor mixture of solvents, one or more fillers, one or more binders, one ormore surfactants, one or more humectants, one or more lubricants, one ormore disintegrants, one or more colorants, one or more antimicrobialagents, one or more antioxidants, one or more pH modifiers and one ormore flavoring agents.

Solvents that may be used in the compositions of the invention include,but are not limited to, various grades of liquid polyethylene glycol(PEG) including PEG 200, PEG 300, PEG 400 and PEG 540; propylenecarbonate; propylene glycol; triglycerides including, but not limited tocaprylic/capric triglyceride, caprylic/capric/linoleic triglyceride(e.g. MIGLYOL® 810 and 812, caprylic/capric/succinic triglyceride,propylene glycol dicaprylate/dicaprate, and the like; water, sorbitolsolution, glycerol caprylate/caprate and polyglycolized glycerides(GELUCIRE®), or a combination thereof.

Various fillers known in the art may be used in the soft chewablecompositions of the invention. Fillers include, but are not limited to,corn starch, pre-gelatinized corn starch, soy protein fines, corn cob,and corn gluten meal, and the like. In some embodiments, a combinationof two or more fillers may be used in the compositions.

Binders that may be used in the compositions of the invention include,but are not limited to, polyvinylpyrrolidone (e.g. Povidone),cross-linked polyvinylpyrrolidone (Crospovidone), polyethylene glycolsof various grades including PEG 3350, PEG 4000, PEG 6000, PEG 8000 andeven PEG 20,000, and the like; co-polymers of vinylpyrrolidone and vinylacetate (e.g. Copovidone) such as the product sold by BASF by thetradename Kollidon® VA 64 and the like; starch such as potato starch,tapioca starch or corn starch; molasses, corn syrup, honey, maple syrupand sugars of various types; or a combination of two or more binders.

Humectants that may be used in the compositions include, but are notlimited to, glycerol (also referred to herein as glycerin), propyleneglycol, cetyl alcohol and glycerol monostearate, and the like.Polyethylene glycols of various grades may also be used as humectants.

Surfactants may be present in the chewable composition at concentrationsof about 0.1% to about 10% (w/w), about 1% to about 10% (w/w) or about5% to about 10% (w/w). More typically, surfactants may be present atconcentrations of about 0.1% to about 5% (w/w) or about 1 to about 5%(w/w). Examples of surfactants that may be used in the compositionsinclude, but are not limited to, glyceryl monooleate, polyoxyethylenesorbitan fatty acid esters, sorbitan esters including sorbitanmonooleate (Span® 20), polyvinyl alcohol, polysorbates includingpolysorbate 20 and polysorbate 80, d-α-tocopherol polyethylene glycol1000 succinate (TPGS), sodium lauryl sulfate, co-polymers of ethyleneoxide and propylene oxide (e.g. poloxamers such as LUTROL® F87 and thelike), polyethylene glycol castor oil derivatives including polyoxyl 35castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castor oil(Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor®RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride estersincluding glycerol caprylate/caprate (CAPMUL® MCM), polyglycolizedglycerides (GELUCIRE®), PEG 300 caprylic/capric glycerides (Softigen®767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleicglycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil®M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl40 stearate (PEG 1750 monostearate, and the like. Polyethylene glycolstearates (synonyms include macrogol stearates, polyoxylstearates,polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3,9005-08-7) are mixtures of mono- and distearate esters of mixedpolyoxyethylene polymers. Polyethylene glycol hydroxystearate is amixture of mono- and diesters of hydroxystearic acid with polyethyleneglycols. One polyethylene glycol hydroxystearate that may be used in thecompositions is polyethylene glycol 12-hydroxystearate. In anotherembodiment, the compositions may include the surfactant polyethyleneglycol 15 12-hydroxystearate (Solutol® HS 15 from BASF), a mixture ofmono- and diesters of 12-hydroxystearic acid with 15 moles of ethyleneoxide. Again, these compounds, as well as their amounts are well knownin the art. In another embodiment of the invention, the compositions mayinclude polyoxyl 35 castor oil (Cremophor® EL) as a surfactant. In otherembodiments, the chewable compositions may include polyoxyl 40hydrogenated castor oil (Cremophor® RH 40) or polyoxyl 60 hydrogenatedcastor oil (Cremophor® RH60) as surfactants. The compositions of theinvention may also include a combination of surfactants.

The chewable compositions may contain other inert ingredients such asantioxidants, preservatives, or pH stabilizers. These compounds are wellknown in the composition art. Antioxidants may be added to thecompositions of the invention to inhibit degradation of the activeagents. Suitable antioxidants include, but are not limited to, alphatocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid,sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylatedhydroxy anisole), BHT (butylated hydroxy toluene) monothioglycerol andthe like.

The chewable compositions of the invention may also include one or morelubricants and/or processing aids. In some cases, thelubricant/processing aid may also behave as a solvent, and accordingly,there some of the components of the inventive compositions may have dualfunctions. Lubricants/processing aids include, but are not limited topolyethylene glycols of various molecular weight ranges including PEG3350 (Dow Chemical) and PEG 4000, corn oil, mineral oil, hydrogenatedvegetable oils (STEROTEX or LUBRITAB), peanut oil and/or castor oil.

Many flavoring agents may be used in the compositions of the inventionto improve the palatability of the oral veterinary compositions.Preferred flavoring agents are those that are not derived from animalsources. In various embodiments, flavoring components derived fromfruit, meat (including, but not limited to pork, beef, chicken, fish,poultry, and the like), vegetable, cheese, bacon, cheese-bacon and/orartificial flavorings may be used. A flavoring component is typicallychosen based upon consideration related to the organism that will beingesting the soft chew. For example, a horse may prefer an appleflavoring component, while a dog may prefer a meat flavoring component.Although flavoring components derived from non-animal sources arepreferred, in some embodiments, natural flavors containing beef or liverextracts, etc., may be used such as braised beef flavor artificialpowdered beef flavor, roast beef flavor and corned beef flavor amongothers.

In another embodiment of the invention, the active composition may beadministered via an oral drench. Drench compositions are those in whichthe liquid-containing compositions of the invention are administered tothe mouth or throat of the animal.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase maybe a vegetableoil, for example, olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin or mixtures of these. Suitable emulsifyingagents include naturally-occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monooleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment, the composition of the invention may be in the formof a microemulsion. Microemulsions are well suited as the liquid carriervehicle. Microemulsions are quaternary systems comprising an aqueousphase, an oily phase, a surfactant and a co-surfactant. They aretranslucent and isotropic liquids.

Microemulsions are composed of stable dispersions of micro droplets ofthe aqueous phase in the oily phase or conversely of micro droplets ofthe oily phase in the aqueous phase. The size of these micro dropletsmay be less than 200 nm (1000 to 100,000 nm for emulsions). Theinterfacial film may be composed of an alternation of surface-active(SA) and co-surface-active (Co-SA) molecules which, by lowering theinterfacial tension, allows the microemulsion to be formedspontaneously.

In one embodiment of the oily phase, the oily phase may be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase may be comprised oftriglycerides; in another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. In another embodiment of the oily phasemay represent a % v/v range of about 2 to about 15%; about 7 to about10%; and about 8 to about 9% v/v of the microemulsion.

The aqueous phase may include, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment, the glycol may be propylene glycol,diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether ormixtures thereof. Generally, the aqueous phase will represent aproportion from about 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion may include diethylene glycolmonoethyl ether, dipropylene glycol monomethyl ether, polyglycolideC₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In addition to thesesurfactants, the co-surfactants may include short-chain alcohols, suchas ethanol and propanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and co-surfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same composition. In one embodiment for the amount ofsurfactant/co-surfactant, the co-surfactant to surfactant ratio will befrom about 1/7 to about ½. In another embodiment for the amount ofco-surfactant, there will be from about 25 to about 75% v/v ofsurfactant and from about 10 to about 55% v/v of co-surfactant in themicroemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents include naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water may provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchcompositions may also contain a demulcent, a preservative, flavoringagent(S) and/or coloring agent(S).

In another embodiment of the invention, the composition may be in pasteform. Examples of embodiments in a paste form include, but are notlimited to, those described in U.S. Pat. Nos. 6,787,342 and 7,001,889(each of which are incorporated herein by reference). In addition to thecompounds of the invention, the paste may further contain fumed silica;a viscosity modifier; a carrier; optionally, an absorbent; andoptionally, a colorant, stabilizer, surfactant, or preservative.

In one embodiment of the composition, the composition may be a pastecontaining the compounds of the invention, fumed silica, a viscositymodifier, an absorbent, a colorant; and a hydrophilic carrier which istriacetin, a monoglyceride, a diglyceride, or a triglyceride.

The paste may also include a viscosity modifier. Suitable viscositymodifiers include, but are not limited to, polyethylene glycols (PEG)including, but not limited to, PEG 200, PEG 300, PEG 400, PEG 600;monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxyethylene (20) sorbitan mono-oleate (polysorbate 80 or Tween 80),or poloxamers (e.g., Pluronic L 81); an absorbent such as magnesiumcarbonate, calcium carbonate, starch, and cellulose and its derivatives;and a colorant including, but not limited to, titanium dioxide ironoxide, or FD&C Blue #1 Aluminum Lake.

In some embodiments, the compositions may be in the form of a sterileinjectable composition. The injectable composition may be a solution inorganic solvents or an aqueous or oleaginous suspension. This suspensionmay be formulated according to the known art using those suitabledispersing or wetting agents and suspending agents which have beenmentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butane diol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. Co-solvents such as ethanol, propylene glycol, glycerol formalor polyethylene glycols may also be used. Preservatives, such as phenolor benzyl alcohol, may be used.

In addition, sterile, fixed oils may be conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

In another embodiment, the present invention provides for long-actinginjectable compositions comprising an isoxazoline compound of formula(Id), a poloxamer and, optionally, a co-solvent. The long-actingcompositions comprising an isoxazoline compound of formula (Id), apoloxamer and a co-solvent, have been surprisingly discovered to bestable and effective against a broad spectrum of ectoparasites, andpossibly also endoparasites if another active is included, for anextended period of time; e.g., a period from three (3) to six (6) monthsor longer while exhibiting favorable properties with respect to the siteof injection.

Poloxamers are a family of synthetic block copolymers of ethylene oxideand propylene oxide. Poloxamers may be liquid, a milky white paste or apowder and are represented by the following structure:

where a is an integer between 2 and 130 and b is an integer between 15and 67 (see, U.S. Pat. No. 3,740,421). Poloxamer are available fromcommercial sources such as BASF and Croda. An example of a poloxamer isP-124 which is a solid at room temperature. In one embodiment, poloxamerP-124 has the values a=12 and b=20. Other poloxamers include P-128 (a=38and b=29), P-181 (a=3 and b=30) P-188 (a=80 and b=27), P-237 (a=64 andb=37), P338 (a=141 and b=44) and P407 (a=101 and b=56).

The co-solvents used in the long-acting injectable compositionscomprising a compound of formula (Id) and a poloxamer may be a single ora blend of co-solvents. In one embodiment, the co-solvents used in thelong-acting injectable compositions of the present invention includepolar solvents that are miscible in water. Non-limiting examples ofthese co-solvents include ethanol, isopropanol, benzyl alcohol, glycolethers (e.g., including, but limited to, diethyleneglycol monoethylether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butylether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like), liquid polyethyleneglycols (PEGs) (for example, PEG 400), propylene glycol, carbonates(e.g., propylene carbonate), 2-pyrrolidone, N-methylpyrrolidone,dimethyl isosorbide (DMI), dimethylacetamide, dimethylsulfoxide,glycerol formal or a mixture of at least two of these solvents.

In one embodiment, the long-acting compositions of the inventioncomprise a polar protic solvent including, but not limited to, analcohol such as ethanol, isopropanol or a glycol or glycol ether. Inanother embodiment, the long-acting injectable compositions of theinvention comprise a polar aprotic solvent such as N-methylpyrrolidone,dimethyl isosorbide, dimethylacetamide, dimethylsulfoxide or propylenecarbonate.

In yet another embodiment of the invention, the long-acting injectablecompositions of the invention include non-water miscible co-solvents.Non-limiting examples of these co-solvents include benzyl benzoate,ethyl acetate, triacetin, lipids, triglycerides including medium chaintriglycerides such C₈-C₁₀ triglycerides such as capric/caprilictriglycerides, propylene glycol derivatives (e.g. propylene glycolmonolaurate), caprylocaproyl polyoxyl-8 glycerides (Labrasol) (non-ionicwater dispersible surfactant, isopropyl myristate, or a mixture of atleast two of these co-solvents. In one embodiment, the compositionsinclude a protic solvent that is not completely miscible with waterincluding, but not limited to, benzyl alcohol.

In another embodiment, the long-acting injectable composition of theinvention may include neutral oils as a co-solvent. Neutral oils aretriglycerides of fractionated plant fatty acids with chain lengths of C₈to C₁₀. Two commercially available products are known as MIGLYOL® 810and MIGLYOL®812. In another embodiment, the neutral oil is atriglyceride of fractionated plant fatty acids with chain lengths of C₈and C₁₀ combined with linoleic acid (about 4-5%). A commerciallyavailable product is known as MIGLYOL® 818. In yet another embodiment,the neutral oil is a glycerin ester of fractionated plant fatty acidswith chain lengths of C₈ and C₁₀ combined with succinic acid. Acommercially available product is known as MIGLYOL® 829. In anotherembodiment, the neutral oil may be a propylene glycol diester ofsaturated plant fatty acids with chain lengths of C₈ and C₁₀. Acommercially available product is known as MIGLYOL® 840 (propyleneglycol dicaprylate/dicaprate). In yet another embodiment, the co-solventmay be a mixture of two or more neutral oils.

In another embodiment, the present invention provides extended releaseinjectable compositions for the treatment or prevention of parasiteinfections or infestations in an animal comprising an antiparasiticeffective amount of at least one isoxazoline compound of formula (Id), apharmaceutically acceptable polymer and optionally a solvent or mixtureof solvents. The pharmaceutically acceptable polymers in the extendedrelease injectable compositions, include, but are not limited to,polylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyester amides, polyorthoesters,polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, polyphosphazenes, pseudo poly(amides),polyhydroxyalcanoates, polyhydroxybutyrates, polyhydroxyvalerates,polyalkylene oxalates, polyalkylene succinates, poly(malic acid),poly(amino acids), poly(methyl vinyl ether), poly(maleic anhydride),chitin, chitosan, and copolymers, terpolymers, or combinations ormixtures therein including copolymers of polylactides,polycaprolactones, polyglycolides (e.g., poly(lactide-co-glycolide) andcopolymers of polyethylene glycol or methoxy polyethylene glycol withone or more of polycaprolactone, polylactide or any of the otherpolymers/polymer groups mentioned above. Also included are derivativesof pharmaceutically acceptable polymers such as hydroxylated derivativesincluding polycaprolactone diols and the like.

The solvents used in the extended release injectable compositions of theinvention may be a single or a blend of solvents. Non-limiting examplesof these solvents include alcohols such as ethanol, 1-propanol,isopropanol, glycol ethers (e.g., including, but limited to,diethyleneglycol monoethyl ether (DGME, Transcutol®), butyl diglycol,dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether,propylene glycol monomethyl ether, propylene glycol monoethyl ether, andthe like), liquid polyethylene glycols (PEGs) including, but not limitedto, PEG 200, PEG 300 and PEG 400; propylene glycol, glycerol, glycerolesters including glycerol triacetate (triacetin), benzyl benzoate, ethylacetate, cyclic carbonates (e.g., ethylene carbonate and propylenecarbonate), 2-pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide(DMI), dimethylacetamide (DMA), dimethyl formamide (DMF), caprolactam,glycerol formal, acetone, dimethylsulfoxide (DMSO), ethyl acetate, ethyllactate, benzyl benzoate, or a mixture of at least two of thesesolvents.

Topical, dermal and subdermal compositions may include, by way ofnon-limiting example, emulsions, creams, ointments, gels, pastes,powders, shampoos, pour-on compositions, ready-to-use compositions,spot-on solutions and suspensions, dips and sprays. Topical applicationof an inventive compound or of a composition including at least oneinventive compound among active agent(S) therein, in the form of aspot-on, spray-on or pour-on composition, may allow for the inventivecomposition to be absorbed through the skin to achieve systemic levels,distributed through the sebaceous glands or on the surface of the skinachieving levels throughout the coat. When the compound is distributedthrough the sebaceous glands, they may act as a reservoir, whereby theremay be a long-lasting effect (up to several months) effect. Spot-oncompositions are typically applied in a localized region which refers toan area other than the entire animal. In one embodiment, the locationmay be between the shoulders. In another embodiment it may be a stripe,e.g. a stripe from head to tail of the animal.

Pour-on compositions are described in U.S. Pat. Nos. 6,010,710 and9,180,121, both incorporated herein by reference. Pour-on compositionsmay be advantageously oily, and generally comprise a diluent or vehicleand also a solvent (e.g. an organic solvent) for the active ingredientif the latter is not soluble in the diluent.

Organic solvents that can be used in the invention include, but are notlimited to, acetyltributyl citrate, fatty acid esters such as thedimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzylalcohol, ethyl alcohol, butyl diglycol, dimethylacetamide,dimethylformamide, dimethylsulfoxide, dimethyl isosorbide, dipropyleneglycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycolmonoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide,dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols,propylene glycol, 2-pyrrolidone, N-methylpyrrolidone, diethylene glycolmonoethyl ether, ethylene glycol, benzyl benzoate, ethyl acetate,triacetin, C₁-C₁₀ esters of carboxylic acids such as butyl or octylacetate, glycerol formal, dialkyl esters of dicarboxylic acids includingdiethyl sebacate, diisopropyl sebacate, diisopropyl adipate and thelike, and diethyl phthalate, or a mixture of at least two of thesesolvents.

The solvent will be used in proportion with the concentration of theactive agent compound and its solubility in this solvent. It will besought to have the lowest possible volume. The vehicle makes up thedifference to 100%.

A vehicle or diluent for the compositions may include dimethyl sulfoxide(DMSO), glycol derivatives such as, for example, propylene glycol,glycol ethers, polyethylene glycols or glycerol. As vehicle or diluent,mention may also be made of plant oils such as, but not limited tosoybean oil, groundnut oil, castor oil, corn oil, cotton oil, olive oil,rape seed oil, sunflower oil, etc.; mineral oils such as, but notlimited to, petrolatum, paraffin, silicone, etc.; aliphatic or cyclichydrocarbons or alternatively, for example, medium-chain (such as C₈ toC₁₂) triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent may be added. In one embodiment, the emollientand/or spreading and/or film-forming agent may be:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;lecithin, sodium carboxymethylcellulose, silicone oils,polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils),for example those containing silanol functionalities, or a 45V2 oil,

(b) anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulfates (e.g. sodium lauryl sulfate and sodium cetylsulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulphosuccinate;fatty acids (e.g. those derived from coconut oil),

(c) cationic surfactants include water-soluble quaternary ammonium saltsof formula N+R′R″R″′R″″, Y″ in which the radicals R are optionallyhydroxylated hydrocarbon radicals and Y is an anion of a strong acidsuch as the halide, sulfate and sulfonate anions; cetyltrimethylammoniumbromide is among the cationic surfactants which can be used,

(d) amine salts of formula N⁺HR′R″R″′ in which the radicals R areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants which can be used,

(e) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g. polysorbate 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,

(f) amphoteric surfactants such as the substituted lauryl compounds ofbetaine; or

(g) a mixture of at least two of these agents.

In one embodiment of the amount of emollient, the emollient used may bein a proportion of from about 0.1 to 50% or 0.25 to 5%, by volume. Inanother embodiment, the emollient used may be in a proportion of fromabout 0.1% to about 30%, about 1% to about 30%, about 1% to about 20%,or about 5% to about 20% by volume.

In another embodiment of the invention, the composition may be in theform of a ready-to-use spot-on solution form as is described in U.S.Pat. Nos. 6,395,765 and 9,180,121, both incorporated herein byreference. In addition to the compounds of the invention, theready-to-use solution may contain a crystallization inhibitor and anorganic solvent or a mixture of organic solvents. In some embodiments,water may be included with the organic solvent.

In various embodiments of the invention, the compositions may include acrystallization inhibitor in an amount of about 1 to about 50% (w/v) orabout 5 to about 40% (w/v) based on the total weight of the composition.In other embodiments, the amount of crystallization inhibitor in theinventive compositions may be about 1% to about 30%, about 5% to about20%, about 1% to about 15%, or about 1% to about 10% (w/w). The type ofcrystallization inhibitor used in the inventive compositions is notlimited as long as it functions to inhibit crystallization of the activeor inactive agents from the composition. For example, in certainembodiments of the invention, a solvent or co-solvent of the compositionmay also function as a crystallization inhibitor if it sufficientlyinhibits the formation of crystals from forming over time when thecomposition is administered.

Crystallization inhibitors which are useful for the invention include,but are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,dimethylformamide, dimethylacetamide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, mannitol, glycerol, sorbitol or polyoxyethylenatedesters of sorbitan; lecithin or sodium carboxymethylcellulose; oracrylic derivatives, such as acrylates or methacrylates or polymers orcopolymers thereof, polyethyleneglycols (PEG) or polymers containingpolyethyleneglycols, such as glycofurol and the like, and others;

(b) anionic surfactants, such as alkaline stearates (e.g. sodium,potassium or ammonium stearate); calcium stearate or triethanolaminestearate; sodium abietate; alkyl sulfates, which include but are notlimited to sodium lauryl sulfate and sodium cetyl sulfate; sodiumdodecylbenzenesulfonate or sodium dioctyl sulphosuccinate; or fattyacids (e.g. coconut oil);

(c) cationic surfactants, such as water-soluble quaternary ammoniumsalts of formula N+R′R″R″′R″″Y⁻, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals and Y⁻ is ananion of a strong acid, such as halide, sulfate and sulfonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used;

(d) amine salts of formula N+HR′R″R″′, in which the R radicals areidentical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used;

(e) non-ionic surfactants, such as optionally polyoxyethylenated estersof sorbitan, e.g. Polysorbate 80, or polyoxyethylenated alkyl ethers;polyethylene glycol stearate, polyoxyethylenated derivatives of castoroil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids or copolymers of ethylene oxide and ofpropylene oxide;

(f) amphoteric surfactants, such as substituted lauryl compounds ofbetaine;

(g) a mixture of at least two of the compounds listed in (a)-(f) above;or

(h) an organic solvent or mixture of solvents which inhibit theformation of crystals or amorphous solid after the composition isadministered.

In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected from the compoundsmentioned above as crystallization inhibitor.

In some embodiments, the organic solvent(S) may have a dielectricconstant of between about 10 and about 35 or between about 20 and about30. In other embodiments, the organic solvent may have a dielectricconstant of between about 10 and about 40 or between about 20 and about30. The content of this organic solvent or mixture of solvents in theoverall composition is not limited and will be present in an amountsufficient to dissolve the desired components to a desiredconcentration. As discussed above, the organic solvent may also functionas a crystallization inhibitor in the composition.

In some embodiments, one or more of the organic solvent(S) may have aboiling point of below about 100° C., or below about 80° C. In otherembodiments, the organic solvent(S) may have a boiling point of belowabout 300° C., below about 250° C., below about 230° C., below about210° C. or below about 200° C.

In some embodiments where there is a mixture of solvents, i.e. a solventand a co-solvent, the solvents may be present in the composition in aweight/weight (W/W) ratio of about 1/50 to about 1/1. Typically thesolvents will be in a ratio of about 1/30 to about 1/1, about 1/20 toabout 1/1, or about 1/15 to about 1/1 by weight. Preferably, the twosolvents will be present in a weight/weight ratio of about 1/15 to about½. In some embodiments, at least one of the solvents present may act asto improve solubility of the active agent or as a drying promoter. Inparticular embodiments, at least one of the solvents will be misciblewith water.

The composition may also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent may be present in a proportion ofabout 0.005 to about 1% (w/v), about 0.01 to about 0.1%, or about 0.01to about 0.05%.

In one embodiment of the film-forming agent, the agents are of thepolymeric type which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants; in anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan and in yet another embodiment ofthe surface-active agent, the agents include the various grades ofpolysorbate, for example Polysorbate 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent may be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned elsewhere.

In another embodiment, the topical compositions include the compoundcrotamiton which may inhibit the crystallization of active agents fromsolution.

The crystallization inhibitor inhibits the formation of crystals on thecoat, and improves the maintenance of the cosmetic appearance of theskin or fur; that is to say without a tendency towards sticking ortowards a sticky appearance, despite the high concentration of activematerial. Substances other than those mentioned herein may be used ascrystallization inhibitors in the present invention. In one embodiment,the effectiveness of the crystallization inhibitor may be demonstratedby a test according to which 0.3 mL of a solution comprising 10% (w/v)of the active agent in an appropriate solvent as defined above, and 10%(w/v) of the compound acting as a crystallization inhibitor are placedon a glass slide at 20° C. for 24 hours, after which fewer than 10crystals, preferably 0 crystals, are seen with the naked eye on theglass slide.

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include but are not limited to butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulfite, propyl gallate, sodium thiosulfate or a mixture of atleast two compounds with antioxidant properties.

The composition adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

The volume of the composition applied will depend on the type of animaland the size of the animal as well as the strength of the compositionand the potency of the active agents. In one embodiment, an amount ofabout 0.3 to about 20 ml of the composition may be applied to theanimal. In other embodiment for the volume, the volume may be about 0.1to about 10 ml, about 0.3 to about 5 ml, about 0.5 ml to about 10 ml, orabout 0.3 to about 3 ml.

In another embodiment of the invention, application of a spot-oncomposition according to the present invention may also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on compositions provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

For spot-on compositions, the carrier may be a liquid carrier vehicle asdescribed in U.S. Pat. Nos. 6,426,333; 6,395,765 (incorporated herein byreference), which in may comprise a solvent or mixture of solventsincluding, but not limited to, acetone, an aliphatic alcohol such asmethanol, ethanol, propanol, butanol, isopropanol, pentanol, hexanol,heptanol, octanol, nonanol, cyclopentanol, cyclohexanol, ethyleneglycol, propylene glycol and the like; an aromatic alcohol such asphenol, cresol, naphthol, benzyl alcohol and the like; acetonitrile,butyl diglycol, an organic amide such as dimethylacetamide,dimethylformamide, monomethylacetamide, 2-pyrrolidone,N-methylpyrrolidone, vinylpyrrolidone and the like; propylene orethylene carbonate, dimethylsulfoxide (DMSO), a glycol polymer or anether thereof, such as polyethylene glycol (PEG) of various grades,polypropylene glycols of various grades, dipropylene glycol n-butylether, ethylene glycol monoethyl ether, ethylene glycol monomethylether, dipropylene glycol monomethyl ether, diethylene glycol monoethylether, ethylene glycol, diethyl phthalate fatty acid esters, such as thediethyl ester or diisobutyl adipate, or a mixture of at least two ofthese solvents.

In another embodiment, the solvents used for the spot-on or pour-oncompositions of the invention include those described in U.S. Pat. No.9,180,121 (incorporated by reference). Solvents for the spot-on orpour-on compositions may include, but are not limited to, carboxylicacid esters, diesters of dicarboxylic acids, fatty acid esters ordiesters of fatty diacids, or a combination thereof, including, but notlimited to, isopropyl palmitate, isostearyl lactate, diisopropyladipate, dibutyl adipate, diethyl sebacate, dibutyl sebacate, octylpalmitate, polyethylene glycol (PEG) stearate and cetearyl octanoate;oils including, but not limited to, mineral oil, diglycerides,triglycerides, jojoba oil, lecithin and castor oil, or a combinationthereof; long chain aliphatic alcohols such as isostearyl alcohol andthe like; fatty alcohols and their esters, including for example, cetylalcohol, cetearyl alcohol and the like, or a combination thereof;polyethylene glycols of different molecular weight ranges including, butnot limited to, PEG 300, PEG 400, PEG 600 and PEG 1000, or a combinationthereof; and glycol ethers including, but not limited to,diethyleneglycol monoethyl ether (Transcutol®), butyl diglycol,propylene glycol monomethyl ether, propylene glycol monoethyl ether,dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether and dipropylene glycol monomethylether, or a combination thereof; or a combination of two or more ofthese solvents.

Excipients that may promote the containment of the active agent in theskin for longer periods of time and may be included in the compositionsof the invention include, but are not limited to, mixed esters ofsucrose and carboxylic acids including sucrose acetate isobutyrate (SAB)and the like; low temperature melting waxes, hydrogenated vegetableoils, caprylic/capric glycerides; glycerol esters, including forexample, triacetin, glycerol monooleate, glycerol monolinoleate,glycerol stearate, glyceryl distearate and the like; triglycerides,including for example, caprylic, capric/myristic/stearic triglyceride;thermoreversible polymers, such as Pluronic and poloxamers, includingfor example, Lutrol F127 by itself or in mixture with other poloxamers;or a combination thereof.

In another embodiment of the invention the pharmaceutically acceptablecarrier for the topical compositions comprise a mixture of a diester ofa dicarboxylic acid alone or in combination with one or more ofadditional solvents listed above, and/or an “oily” lipophilic substance,including a liquid or low melting lipophilic active agent such as(S)-methoprene, pyriproxyfen and/or permethrin; and/or a mixed ester ofsucrose and carboxylic acids including a mixed ester of sucrose andacetic and isobutyric acids such as sucrose acetate isobutyrate (SAB),and/or low melting waxes and/or hard fats.

In one embodiment, the diester of a dicarboxylic acid in the topicalcompositions is diethyl sebacate or diisopropyl adipate. In anotherembodiment, the blend of solvents comprising a dicarboxylic acid estercomprises a glycol or polyglycol, or a glycol or polyglycol ether orester including, but not limited to, ethylene glycol (EG), propyleneglycol (PG), liquid polyoxyethylene glycols (PEGs) of various gradesincluding PEG 400, EG or PG monocaprylate, EG or PG caprylate, EG or PGmonolaurate, EG or PG dicaprylate/dicaprate, diethyleneglycol monoethylether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butylether, ethyleneglycol monoethyl ether, ethyleneglycol monomethyl ether,dipropylene glycol monomethyl ether, propylene glycol monomethyl ether,propylene glycol monoethyl ether, and the like, or a combinationthereof; an ether including, but not limited to, dimethyl isosorbide; anester or di-ester including, but not limited to, triacetin, lauryllactate; and other solvents including glycerol formal, or mixturesthereof.

In preferred embodiments, the carrier for the topical compositionscomprises a dialkyl ester of a dicarboxylic acid such as diethylsebacate, diisopropyl sebacate, diisopropyl adipate, dibutyl adipate, ora combination thereof, alone or in combination with solvents selectedfrom:

-   -   a) a propylene glycol (PG) ester including PG monocaprylate, PG        caprylate, PG monolaurate, PG dicaprylate/dicaprate, or a        combination thereof;    -   b) an ether solvent including dimethyl isosorbide, diethylene        glycol monoethyl ether (also known as DGME or Transcutol®), or a        combination thereof;    -   c) a carboxylic acid ester including, but not limited to,        triacetin, lauryl lactate, isopropyl palmitate, diisopropyl        sebacate, or a combination thereof; and    -   d) other “oily” or lipophilic organic solvents including        glycerol formal and the like.

In some embodiments, the amount the additional solvents combined withthe carboxylic acid ester or diester of a dicarboxylic acid are presentin an amount of at least about 1% (v/v), at least about 5% (v/v), atleast about 9.0% (v/v), at least about 13% (v/v), at least about 17%(v/v) or at least about 20% (v/v). Preferably the additional solventswill be in an amount of at least about 9% (v/v).

In other embodiments, the additional solvents will be present in anamount of about 5-70% (v/v), about 10-60% (v/v), about 10-50% (v/v),about 15-60% (v/v) or about 15-50% (v/v).

In preferred embodiments, the additional solvents will be present in anamount of about 20-70% (v/v), about 20-60% (v/v), about 20-50% (v/v) orabout 25-50% (v/v).

In some embodiments, the liquid carrier vehicle may optionally contain acrystallization inhibitor including, but not limited to, those describedin (a) to (h) above, or a compound that may act both as a solvent and acrystallization inhibitor (as defined above), or a mixture of thesecrystallization inhibitors.

Spot-on compositions may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on composition may be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These compositions will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host.

Dosage forms may typically contain from about 0.1 mg to about 5 g. Inother embodiments, the dosage form may contain about 0.5 mg to about 5 gof an active agent. In one embodiment of the dosage form, the dosage maycontain from about 1 mg to about 500 mg of an active agent, typicallyabout 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg,about 400 mg, about 500 mg, about 600 mg, about 800 mg, or about 1000mg.

In one embodiment of the invention, the active agent may be present inthe composition at a concentration of about 0.05 to about 10%weight/volume. In another embodiment of the invention, the active agentmay be present in the composition as a concentration from about 0.1 toabout 2% weight/volume. In yet another embodiment of the invention, theactive agent may be present in the composition as a concentration fromabout 0.25 to about 1.5% weight/volume. In still another embodiment ofthe invention, the active agent may be present in the composition as aconcentration about 1% weight/volume.

II. Methods of Treatment:

As discussed above, the compounds of formula (Id) are effective againstectoparasites and may be used to treat and prevent parasiticinfestations in or on animals. In one embodiment, the present inventionprovides a method of treating or preventing an ectoparasite infestationin or on an animal (e.g. a mammal or bird) comprising administering anectoparasiticidally effective amount of a compound of formula (Id), orpharmaceutically acceptable salts thereof, or a composition comprisingthe compound, to the animal. In another embodiment, the methods of theinvention comprise administering an effective amount of a compound offormula (Ie) or (S)-Ie, or a pharmaceutically acceptable salt thereof,to the animal.

In another embodiment when the compounds of formula (Id) areadministered in combination with compounds that are active againstendoparasites, the invention provides a method for treating orpreventing an endoparasitic infection and an ectoparasitic infestationin and on an animal, comprising administering a composition comprisingan effective amount of a compound of formula (Id) in combination with aneffective amount of at least a second active agent, or pharmaceuticallyacceptable salts thereof, to the animal.

Mammals which can be treated include but are not limited to humans,cats, dogs, cattle, chickens, cows, bison, deer, goats, horses, llamas,camels, pigs, sheep and yaks. In one embodiment of the invention, themammals treated are humans, cats or dogs.

In one embodiment of the invention, the compositions of the inventioncomprising a compound of formula (Id) in combination with an additionalcompound that is active against endoparasites are effective againstendoparasites that are resistant to active agents of the macrocycliclactone class. In one embodiment, the compounds and compositions of theinvention are effective for controlling Haemonchus contortus, Ostertagiacircumcincta and Trichostrongylus colubriformis in mammals or birds.

In another embodiment, the invention provides a method for treating anparasitic infestation and/or infection in an animal, comprisingadministering an effective amount of a compound of formula (Id) incombination with an effective amount of activators of invertebrate GABAreceptors, including an avermectin or milbemycin, to the animal in needthereof.

Avermectins that may be used in combination with the compounds of theinvention include, but are not limited to abamectin, dimadectin,doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin,and selamectin. Milbemycins compounds that may be used in combinationwith the compounds of the invention include, but are not limited to,milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin.Also included are the 5-oxo and 5-oxime derivatives of said avermectinsand milbemycins.

In one embodiment for the treatment against ectoparasites, theectoparasite is from the genera Ctenocephalides, Rhipicephalus,Dermacentor, Ixodes, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes,Psoroptes, Otodectes, Chorioptes, Hypoderma, Damnalinia, Linognathus,Haematopinus, Solenoptes, Trichodectes, and Felicola. The ectoparasitestreated include but are not limited to fleas, ticks, mites, mosquitoes,flies, lice, blowfly and combinations thereof. Specific examples includebut are not limited to cat and dog fleas (Ctenocephalides felis,Ctenocephalides spp. and the like), ticks (Rhipicephalus spp., Ixodesspp., Dermacentor spp., Amblyomma spp. and the like), and mites (Demodexspp., Sarcoptes spp., Otodectes spp. and the like), lice (Trichodectesspp., Cheyletiella spp., Linognathus spp., and the like), mosquitoes(Aedes spp., Culex spp., Anopheles spp., and the like) and flies(Haematobia spp., Musca spp., Stomoxys spp., Dermatobia spp.,Cochliomyia spp., and the like). In yet another embodiment for thetreatment against ectoparasites, the ectoparasite is a flea and/or tick.

Additional examples of ectoparasites that may be controlled with thecompounds of formula (Id) include, but are not limited, to the tickRhipicephalus microplus (cattle tick), Rhipicephalus decoloratus andRhipicephalus annulatus; myiasis such as Dermatobia hominis (known asBerne in Brazil) and Cochliomyia hominivorax (greenbottle); sheepmyiasis such as Lucilia sericata, Lucilia cuprina (known as blowflystrike in Australia, New Zealand and South Africa). Flies proper, namelythose whose adult constitutes the parasite, such as Haematobia irritans(horn fly); lice such as Linognathus vitulorum, etc.; and mites such asSarcoptes scabiei and Psoroptes ovis. The above list is not exhaustiveand other ectoparasites are well known in the art to be harmful toanimals and humans. These include, for example migrating dipterouslarvae.

In one embodiment, when administered with another compound that isactive against endoparasites, the compounds and compositions of theinvention may be used for treating or preventing an endoparasiticinfection of the following parasite: Anaplocephala (Anoplocephala),Ancylostoma, Necator, Ascaris, Brugia, Bunostomum, Capillaria,Chabertia, Cooperia, Cyathostomum, Cylicocyclus, Cylicodontophorus,Cylicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipylidium,Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola,Filaroides, Habronema, Haemonchus, Metastrongylus, Moniezia, Necator,Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia,Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara,Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus,Triodontophorus, Uncinaria, Wuchereria, and combinations thereof.

In another embodiment of the invention, the parasite is Haemonchuscontortus, Ostertagia circumcincta, Trichostrongylus axei,Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus,Dirofilaria immitis, and combinations thereof.

In another embodiment of the invention, the compounds and compositionsof the invention are suitable for controlling pests such as insectsselected from the group consisting of Blatella germanica, Heliothisvirescens, Leptinotarsa decemlineata, Tetramorium caespitum andcombinations thereof.

The phytoparasitic nematodes include, for example, Anguina spp.,Aphelenchoides spp., Belonolaimus spp., Bursaphelenchus spp.,Ditylenchus dipsaci, Globodera spp., Helicotylenchus spp., Heteroderaspp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholussimilis, Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp.,Tylenchulus spp., Tylenchulus semipenetrans, Xiphinema spp.

In addition, with or without the other pesticidal agents added to thecomposition, the invention can also be used to treat other pests whichinclude but are not limited to pests:

(1) from the order of Isopoda, for example Oniscus asellus,Armadillidium vulgare and Porcellio scaber;

(2) from the order of Diplopoda, for example Blaniulus guttulatus;

(3) from the order of Chilopoda, for example Geophilus carpophagus andScutigera spp.;

(4) from the order of Symphyla, for example Scutigerella immaculata;

(5) from the order of Thysanura, for example Lepisma saccharina;

(6) from the order of Collembola, for example Onychiurus armatus;

(7) from the order of Blattaria, for example Blatta orientalis,Periplaneta americana, Leucophaea maderae and Blattella germanica;

(8) from the order of Hymenoptera, for example Diprion spp., Hoplocampaspp., Lasius spp., Monomorium pharaonis and Vespa spp.;

(9) from the order of Siphonaptera, for example Xenopsylla cheopis andCeratophyllus spp.;

(10) from the order of Anoplura (Phthiraptera), for example, Damaliniaspp., Haematopinus spp., Linognathus spp., Pediculus spp., Trichodectesspp.;

(11) from the class of Arachnida, for example, Acarus siro, Aceriasheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp.,Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp.,Dermanyssus gallinae, Eotetranychus spp., Epitrimerus pyri,Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp.,Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychusspp., Ornithodoros spp., Panonychus spp., Phyllocoptruta oleivora,Polyphagotarsonemus latus, Psoroptes spp., Rhipicephalus spp.,Rhizoglyphus spp., Sarcoptes spp., Scorpio maurus, Steneotarsonemusspp., Tarsonemus spp., Tetranychus spp., Vasates lycopersici;

(12) from the class of Bivalva, for example, Dreissena spp.;

(13) from the order of Coleoptera, for example, Acanthoscelidesobtectus, Adoretus spp., Agelastica alni, Agriotes spp., Amphimallonsolstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp.,Anthrenus spp., Apogonia spp., Atomaria spp., Attagenus spp., Bruchidiusobtectus, Bruchus spp., Ceuthorhynchus spp., Cleonus mendicus, Conoderusspp., Cosmopolites spp., Costelytra zealandica, Curculio spp.,Cryptorhynchus lapathi, Dermestes spp., Diabrotica spp., Epilachna spp.,Faustinus cubae, Gibbium psylloides, Heteronychus arator, Hylamorphaelegans, Hylotrupes bajulus, Hypera postica, Hypothenemus spp.,Lachnosterna consanguinea, Leptinotarsa decemlineata, Lissorhoptrusoryzophilus, Lixus spp., Lyctus spp., Meligethes aeneus, Melolonthamelolontha, Migdolus spp., Monochamus spp., Naupactus xanthographus,Niptus hololeucus, Oryctes rhinoceros, Oryzaephilus surinamensis,Otiorrhynchus sulcatus, Oxycetonia jucunda, Phaedon cochleariae,Phyllophaga spp., Popillia japonica, Premnotrypes spp., Psylliodeschrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha dominica,Sitophilus spp., Sphenophorus spp., Sternechus spp., Symphyletes spp.,Tenebrio molitor, Tribolium spp., Trogoderma spp., Tychius spp.,Xylotrechus spp., Zabrus spp.;

(14) from the order of Diptera, for example, Aedes spp., Anopheles spp.,Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata,Chrysomyia spp., Cochliomyia spp., Cordylobia anthropophaga, Culex spp.,Cuterebra spp., Dacus oleae, Dermatobia hominis, Drosophila spp., Fanniaspp., Gastrophilus spp., Hylemyia spp., Hyppobosca spp., Hypoderma spp.,Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp.,Oscinella frit, Pegomyia hyoscyami, Phorbia spp., Stomoxys spp., Tabanusspp., Tannia spp., Tipulapaludosa, Wohlfahrtia spp.;

(15) from the class of Gastropoda, for example, Arion spp., Biomphalariaspp., Bulinus spp., Deroceras spp., Galba spp., Lymnaea spp.,Oncomelania spp., Succinea spp.;

(16) from the class of helminths, for example, Ancylostoma duodenale,Ancylostoma ceylanicum, Ancylostoma braziliensis, Ancylostoma spp.,Ascaris lumbricoides, Ascaris spp., Brugia malayi, Brugia timori,Bunostomum spp., Chabertia spp., Clonorchis spp., Cooperia spp.,Dicrocoelium spp, Dictyocaulus filaria, Diphyllobothrium latum,Dracunculus medinensis, Echinococcus granulosus, Echinococcusmultilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp.,Heterakis spp., Hymenolepis nana, Hyostrongulus spp., Loa Loa,Nematodirus spp., Oesophagostomum spp., Opisthorchis spp., Onchocercavolvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp.,Strongyloides fuelleborni, Strongyloides stercoralis, Strongyloidesspp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinellanativa, Trichinella britovi, Trichinella nelsoni, Trichinellapseudopsiralis, Trichostrongulus spp., Trichuris trichiura, Wuchereriabancrofti;

(17) from the order of Heteroptera, for example, Anasa tristis,Antestiopsis spp., Blissus spp., Calocoris spp., Camnpylomma livida,Cavelerius spp., Cimex spp., Creontiades dilutus, Dasynus piperis,Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistusspp., Eurygaster spp., Heliopeltis spp., Horcias nobilellus, Leptocorisaspp., Leptoglossus phyllopus, Lygus spp., Macropes excavatus, Miridae,Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp.,Psallus seriatus, Pseudacysta persea, Rhodnius spp., Sahlbergellasingularis, Scotinophora spp., Stephanitis nashi, Tibraca spp., Triatomaspp.;

(18) from the order of Homoptera, for example, Acyrthosipon spp.,Aeneolanmia spp., Agonoscena spp., Aleurodes spp., Aleurolobusbarodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui,Aonidiella spp., Aphanostigma piri, Aphis spp., Arboridia apicalis,Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani,Bemisia spp., Brachycaudus helichrysii, Brachycolus spp., Brevicorynebrassicae, Calligypona marginata, Carneocephala fulgida, Ceratovacunalanigera, Cercopidae, Ceroplastes spp., Chaetosiphon fragaefolii,Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola,Chrysomphalus ficus, Cicadulina mbila, Coccomytilus halli, Coccus spp.,Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp.,Diaspis spp., Doralis spp., Drosicha spp., Dysaphis spp., Dysmicoccusspp., Empoasca spp., Eriosoma spp., Erythroneura spp., Euscelisbilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterusarundinis, Icerya spp., Idiocerus spp., Idioscopus spp., Laodelphaxstriatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi,Macrosiphum spp., Mahanarva fimbriolata, Melanaphis sacchari,Metcalfiella spp., Metopolophium dirhodum, Monellia costalis,Monelliopsis pecanis, Myzus spp., Nasonovia ribisnigri, Nephotettixspp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga,Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pemphigus spp.,Peregrinus maidis, Phenacoccus spp., Phloeomyzus passerinii, Phorodonhumuli, Phylloxera spp., Pinnaspis aspidistrae, Planococcus spp.,Protopulvinaria pyriformis, Pseudaulacaspis pentagona, Pseudococcusspp., Psylla spp., Pteromalus spp., Pyrilla spp., Quadraspidiotus spp.,Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp.,Scaphoides titanus, Schizaphis graminum, Selenaspidus articulatus,Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina,Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp.,Toxoptera spp., Trialeurodes vaporariorum, Trioza spp., Typhlocyba spp.,Unaspis spp., Viteus vitifolii;

(19) from the order of Isoptera, for example, Reticulitermes spp.,Odontotermes spp.;

(20) from the order of Lepidoptera, for example, Acronicta major, Aedialeucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathrabrassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana,Capua reticulana, Carpocapsa pomonella, Cheimatobia brumata, Chilo spp.,Choristoneura fumiferana, Clysia ambiguella, Cnaphalocerus spp., Eariasinsulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp.,Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp.,Hofmannophila pseudospretella, Homona magnanima, Hyponomeuta padella,Laphygma spp., Lithocolletis blancardella, Lithophane antennata,Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestrabrassicae, Mocis repanda, Mythimna separata, Oria spp., Oulema oryzae,Panolis flammea, Pectinophora gossypiella, Phyllocnistis citrella,Pieris spp., Plutella xylostella, Prodenia spp., Pseudaletia spp.,Pseudoplusia includens, Pyrausta nubilalis, Spodoptera spp., Thermesiagemmatalis, Tinea pellionella, Tineola bisselliella, Tortrix viridana,Trichoplusia spp.;

(21) from the order of Orthoptera, for example, Acheta domesticus,Blatta orientalis, Blattella germanica, Gryllotalpa spp., Leucophaeamaderae, Locusta spp., Melanoplus spp., Periplaneta americana,Schistocerca gregaria;

(22) from the order of Thysanoptera, for example, Baliothrips biformis,Enneothrips flavens, Frankliniella spp., Heliothrips spp., Hercinothripsfemoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothripsspp., Taeniothrips cardamoni, Thrips spp.; (23) from the class ofProtozoa, for example, Eimeria spp.

In each aspect of the invention, the compounds and compositions of theinvention can be applied against a single pest or combinations thereof.

Non-Veterinary Applications

For use in a method for combating pests that damage plants, plantpropagation material and crops, or material derived from wood, accordingto the present invention, the compounds of formula (Id) can be convertedinto the customary compositions, e.g. solutions, emulsions, suspensions,dusts, powders, pastes, granules and directly sprayable solutions. Theuse form depends on the particular purpose and application method.Formulations and application methods are chosen to ensure in each case afine and uniform distribution of the compound of the formula (Id)according to the present invention.

I. Agricultural Compositions

The compositions are prepared in a known manner (see e.g. for reviewU.S. Pat. No. 3,060,084, EP-A 707 445 (for liquid concentrates),Browning, “Agglomeration”, Chemical Engineering, Dec. 4, 1967, 147-48,Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York,1963, pages 8-57 and et seq. WO 91/13546, U.S. Pat. Nos. 4,172,714,4,144,050, 3,920,442, 5,180,587, 5,232,701, 5,208,030, GB 2,095,558,U.S. Pat. No. 3,299,566, Klingman, Weed Control as a Science, John Wileyand Sons, Inc., New York, 1961, Hance et al., Weed Control Handbook, 8thEd., Blackwell Scientific Publications, Oxford, 1989 and Mollet, H.,Grubemann, A., Formulation technology, Wiley VCH Verlag GmbH, Weinheim(Germany), 2001, 2. D. A. Knowles, Chemistry and Technology ofAgrochemical Formulations, Kluwer Academic Publishers, Dordrecht, 1998(ISBN 0-7514-0443-8, all of which are hereby incorporated by referencein their entirety), for example by extending the active compound withauxiliaries suitable for the composition of agrochemicals, such assolvents and/or carriers, if desired emulsifiers, surfactants anddispersants, preservatives, antifoaming agents, anti-freezing agents,for seed treatment composition also optionally colorants and/or bindersand/or gelling agents. The following solvents/carriers are suitable forcompositions of the invention:

-   -   solvents such as water, aromatic solvents (for example Solvesso        products, xylene and the like), paraffins (for example mineral        fractions), alcohols (for example methanol, butanol, pentanol,        benzyl alcohol), ketones (for example cyclohexanone,        gamma-butyrolactone), pyrrolidones (N-methylpyrrolidone (NMP),        N-octylpyrrolidone NOP), acetates (glycol diacetate), alkyl        lactates, lactones such as g-butyrolactone, glycols, fatty acid        dimethylamides, fatty acids and fatty acid esters,        triglycerides, oils of vegetable or animal origin and modified        oils such as alkylated plant oils. In principle, solvent        mixtures may also be used.    -   carriers such as ground natural minerals and ground synthetic        minerals, such as silica gels, finely divided silicic acid,        silicates, talc, kaolin, attaclay, limestone, lime, chalk, bole,        loess, clay, dolomite, diatomaceous earth, calcium sulfate and        magnesium sulfate, magnesium oxide, ground synthetic materials,        fertilizers, such as, for example, ammonium sulfate, ammonium        phosphate, ammonium nitrate, ureas and products of vegetable        origin, such as cereal meal, tree bark meal, wood meal and        nutshell meal, cellulose powders and other solid carriers.

Suitable emulsifiers include non-ionic and anionic emulsifiers (forexample polyoxyethylene fatty alcohol ethers, alkylsulfonates andarylsulfonates).

Examples of suitable dispersants include lignin-sulfite waste liquorsand methylcellulose.

Suitable surfactants include alkali metal, alkaline earth metal andammonium salts of lignosulfonic acid, naphthalenesulfonic acid,phenolsulfonic acid, dibutylnaphthalenesulfonic acid,alkylarylsulfonates, alkyl sulfates, alkylsulfonates, fatty alcoholsulfates, fatty acids and sulfated fatty alcohol glycol ethers,furthermore condensates of sulfonated naphthalene and naphthalenederivatives with formaldehyde, condensates of naphthalene or ofnaphthalenesulfonic acid with phenol and formaldehyde, polyoxyethyleneoctylphenyl ether, ethoxylated isooctylphenol, octylphenol, nonylphenol,alkylphenyl polyglycol ethers, tributylphenyl polyglycol ether,tristearylphenyl polyglycol ether, alkylaryl polyether alcohols, alcoholand fatty alcohol/ethylene oxide condensates, ethoxylated castor oil,polyoxyethylene alkyl ethers, ethoxylated polyoxypropylene, laurylalcohol polyglycol ether acetal, sorbitol esters,

In some embodiments, anti-freezing agents such as glycerin, ethyleneglycol, propylene glycol and bactericides such as can be added to thecomposition.

In other embodiments, antifoaming agents may be included in thecompositions. Suitable antifoaming agents include antifoaming agentsbased on silicon or magnesium stearate.

The compositions of the invention may comprise preservatives. Suitablepreservatives include, for example, dichlorophenyl and benzyl alcoholhemiformal

In other embodiments, the compositions of the invention may includethickeners known in the art. Suitable thickeners include compounds whichconfer a pseudoplastic flow behavior to the composition, i.e. highviscosity at rest and low viscosity in the agitated stage. Thesethickeners include, for example, of commercial thickeners based onpolysaccharides, such as Xanthan Gum® (Kelzan® from Kelco), Rhodopol®23(Rhone Poulenc) or Veegum® (from R. T. Vanderbilt), or organicphyllosilicates, such as Attaclay® (from Engelhardt). Antifoam agentssuitable for the dispersions according to the invention are, forexample, silicone emulsions (such as, for example, Silikon® SRE, Wackeror Rhodorsil® from Rhodia), long-chain alcohols, fatty acids,organofluorine compounds and mixtures thereof. Biocides can be added tostabilize the compositions according to the invention against attack bymicroorganisms. Suitable biocides are, for example, based onisothiazolones such as the compounds marketed under the trademarksProxel® from Avecia (or Arch) or Acticide® RS from Thor Chemie andKathon® MK from Rohm & Haas. Suitable antifreeze agents are organicpolyols, for example ethylene glycol, propylene glycol or glycerol.These are usually employed in amounts of not more than 10% by weight,based on the total weight of the active compound composition. Ifappropriate, the active compound compositions according to the inventionmay comprise 1 to 5% by weight of buffer, based on the total amount ofthe composition prepared, to regulate the pH, the amount and type of thebuffer used depending on the chemical properties of the active compoundor the active compounds. Examples of buffers are alkali metal salts ofweak inorganic or organic acids, such as, for example, phosphoric acid,boronic acid, acetic acid, propionic acid, citric acid, fumaric acid,tartaric acid, oxalic acid and succinic acid.

Substances which are suitable for the preparation of directly sprayablesolutions, emulsions, pastes or oil dispersions are mineral oilfractions of medium to high boiling point, such as kerosene or dieseloil, furthermore coal tar oils and oils of vegetable or animal origin,aliphatic, cyclic and aromatic hydrocarbons, for example toluene,xylene, paraffin, tetrahydronaphthalene, alkylated naphthalenes or theirderivatives, methanol, ethanol, propanol, butanol, cyclohexanol,cyclohexanone, isophorone, strongly polar solvents, for example dimethylsulfoxide, N-methylpyrrolidone and water.

Powders, materials for spreading and dusts can be prepared by mixing orconcomitantly grinding the active substances with a solid carrier.

Granules, for example coated granules, impregnated granules andhomogeneous granules, can be prepared by binding the active ingredientsto solid carriers. Examples of solid carriers are mineral earths such assilica gels, silicates, talc, kaolin, attaclay, limestone, lime, chalk,bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate,magnesium sulfate, magnesium oxide, ground synthetic materials,fertilizers, such as, for example, ammonium sulfate, ammonium phosphate,ammonium nitrate, ureas, and products of vegetable origin, such ascereal meal, tree bark meal, wood meal and nutshell meal, cellulosepowders and other solid carriers.

In general, the compositions typically comprise from about 0.01 to about95% by weight, preferably from about 0.1 to about 90% by weight, of theactive ingredient. The active ingredients are employed typically have apurity of from about 90% to about 100%, preferably about 95% to about100% (according to NMR spectrum).

For seed treatment purposes, respective compositions can be diluted 2-10fold leading to concentrations in the ready to use preparations of about0.01 to about 60% by weight active compound by weight, preferably about0.1 to about 40% by weight.

The compound of formula (Id) can be used as such, in the form of theircompositions or the use forms prepared therefrom, for example in theform of directly sprayable solutions, powders, suspensions ordispersions, emulsions, oil dispersions, pastes, dustable products,materials for spreading, or granules, by means of spraying, atomizing,dusting, spreading or pouring. The use forms depend entirely on theintended purposes; they are intended to ensure in each case the finestpossible distribution of the active compounds according to theinvention.

The following are examples of compositions:

1. Products for dilution with water. For seed treatment purposes, suchproducts may be applied to the seed diluted or undiluted.

A) Water-Soluble Concentrates (SL, LS)

10 parts by weight of the active compound is dissolved in 90 parts byweight of water or a water-soluble solvent. As an alternative, wettersor other auxiliaries are added. The active compound dissolves upondilution with water, whereby a composition with 10% (w/w) of activecompound is obtained.B) Dispersible Concentrates (DC)20 parts by weight of the active compound is dissolved in 70 parts byweight of cyclohexanone with addition of 10 parts by weight of adispersant, for example polyvinylpyrrolidone. Dilution with water givesa dispersion, whereby a composition with 20% (w/w) of active compoundsis obtained.C) Emulsifiable Concentrates (EC)15 parts by weight of the active compounds is dissolved in 7 parts byweight of xylene with addition of calcium dodecylbenzenesulfonate andcastor oil ethoxylate (in each case 5 parts by weight). Dilution withwater gives an emulsion, whereby a composition with 15% (w/w) of activecompounds is obtained.D) Emulsions (EW, EO, ES)25 parts by weight of the active compound is dissolved in 35 parts byweight of xylene with addition of calcium dodecylbenzenesulfonate andcastor oil ethoxylate (in each case 5 parts by weight). This mixture isintroduced into 30 parts by weight of water by means of an emulsifiermachine (e.g. Ultraturrax) and made into a homogeneous emulsion.Dilution with water gives an emulsion, whereby a composition with 25%(w/w) of active compound is obtained.E) Suspensions (SC, OD, FS)In an agitated ball mill, 20 parts by weight of the active compound iscomminuted with addition of 10 parts by weight of dispersants, wettersand 70 parts by weight of water or of an organic solvent to give a fineactive compound suspension. Dilution with water gives a stablesuspension of the active compound, whereby a composition with 20% (w/w)of active compound is obtained.F) Water-Dispersible Granules and Water-Soluble Granules (WG, SG)50 parts by weight of the active compound is ground finely with additionof 50 parts by weight of dispersants and wetters and made aswater-dispersible or water-soluble granules by means of technicalappliances (for example extrusion, spray tower, fluidized bed). Dilutionwith water gives a stable dispersion or solution of the active compound,whereby a composition with 50% (w/w) of active compound is obtained.G) Water-Dispersible Powders and Water-Soluble Powders (WP, SP, SS, WS)75 parts by weight of the active compound are ground in a rotor-statormill with addition of 25 parts by weight of dispersants, wetters andsilica gel. Dilution with water gives a stable dispersion or solution ofthe active compound, whereby a composition with 75% (w/w) of activecompound is obtained.H) Gel-Formulation (GF)In an agitated ball mill, 20 parts by weight of the active compound iscomminuted with addition of 10 parts by weight of dispersants, 1 part byweight of a gelling agent wetters and 70 parts by weight of water or ofan organic solvent to give a fine active compound suspension. Dilutionwith water gives a stable suspension of the active compound, whereby acomposition with 20% (w/w) of active compound is obtained.2. Products to be applied undiluted for foliar applications. For seedtreatment purposes, such products may be applied to the seed diluted orundiluted.I) Dustable Powders (DP, DS)5 parts by weight of the active compound are ground finely and mixedintimately with 95 parts by weight of finely divided kaolin. This givesa dustable product having 5% (w/w) of active compound.J) Granules (GR, FG, GG, MG)0.5 part by weight of the active compound is ground finely andassociated with 95.5 parts by weight of carriers, whereby a compositionwith 0.5% (w/w) of active compound is obtained. Current methods areextrusion, spray-drying or the fluidized bed. This gives granules to beapplied undiluted for foliar use.K) ULV Solutions (UL)10 parts by weight of the active compound is dissolved in 90 parts byweight of an organic solvent, for example xylene. This gives a producthaving 10% (w/w) of active compound, which is applied undiluted forfoliar use.

Aqueous use forms can be prepared from emulsion concentrates, pastes orwettable powders (sprayable powders, oil dispersions) by adding water.To prepare emulsions, pastes or oil dispersions, the substances, as suchor dissolved in an oil or solvent, can be homogenized in water by meansof a wetter, tackifier, dispersant or emulsifier. Alternatively, it ispossible to prepare concentrates composed of active substance, wetter,tackifier, dispersant or emulsifier and, if appropriate, solvent or oil,and such concentrates are suitable for dilution with water. The activeingredient concentrations in the ready-to-use products can be variedwithin relatively wide ranges. In general, they are from about 0.0001 toabout 10%, preferably from about 0.01 to about 1%.

The active ingredients may also be used successfully in theultra-low-volume process (ULV), it being possible to apply compositionscomprising over 95% by weight of active ingredient, or even to apply theactive ingredient without additives.

II. Mixtures with Other Actives

In the method of this invention compounds of formula (Id), including inparticular (Ie) and (S)-Ie, may be applied with other activeingredients, for example with other pesticides, insecticides,herbicides, fertilizers such as ammonium nitrate, urea, potash, andsuperphosphate, phytotoxicants and plant growth regulators, safeners andnematicides. These additional ingredients may be used sequentially or incombination with the above-described compositions, if appropriate alsoadded only immediately prior to use (tank mix). For example, theplant(S) may be sprayed with a composition of this invention eitherbefore or after being treated with other active ingredients.

The following list M of pesticides together with which the compoundsaccording to the invention can be used and with which potentialsynergistic effects might be produced, is intended to illustrate thepossible combinations, but not to impose any limitation:

M.1. Organo(thio)phosphate compounds: acephate, azamethiphos,azinphos-ethyl, azinphos-methyl, chlorethoxyfos, chlorfenvinphos,chlormephos, chlorpyrifos, chlorpyrifos-methyl, coumaphos, cyanophos,demeton-S-methyl, diazinon, dichlorvos/DDVP, dicrotophos, dimethoate,dimethylvinphos, disulfoton, EPN, ethion, ethoprophos, famphur,fenamiphos, fenitrothion, fenthion, flupyrazophos, fosthiazate,heptenophos, isoxathion, malathion, mecarbam, methamidophos,methidathion, mevinphos, monocrotophos, naled, omethoate,oxydemeton-methyl, parathion, parathion-methyl, phenthoate, phorate,phosalone, phosmet, phosphamidon, phoxim, pirimiphos-methyl, profenofos,propetamphos, prothiofos, pyraclofos, pyridaphenthion, quinalphos,sulfotep, tebupirimfos, temephos, terbufos, tetrachlorvinphos,thiometon, triazophos, trichlorfon, vamidothion;M.2. Carbamate compounds: aldicarb, alanycarb, bendiocarb, benfuracarb,butocarboxim, butoxycarboxim, carbaryl, carbofuran, carbosulfan,ethiofencarb, fenobucarb, formetanate, furathiocarb, isoprocarb,methiocarb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur,thiodicarb, thiofanox, trimethacarb, XMC, xylylcarb, triazamate;M.3. Pyrethroid compounds: acrinathrin, allethrin, d-cis-transallethrin, d-trans allethrin, bifenthrin, bioallethrin, bioallethrinS-cylclopentenyl, bioresmethrin, cycloprothrin, cyfluthrin,beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin,cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin,zeta-cypermethrin, cyphenothrin, deltamethrin, empenthrin,esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate,flumethrin, tau-fluvalinate, halfenprox, imiprothrin, metofluthrin,permethrin, phenothrin, prallethrin, profluthrin, pyrethrin (pyrethrum),resmethrin, silafluofen, tefluthrin, tetramethrin, tralomethrin,transfluthrin;M.4. Juvenile hormone mimics: hydroprene, kinoprene, methoprene,fenoxycarb, pyriproxyfen;M.5. Nicotinic receptor agonists/antagonists compounds: acetamiprid,bensultap, cartap hydrochloride, clothianidin, dinotefuran,imidacloprid, thiamethoxam, nitenpyram, nicotine, spinosad (allostericagonist), spinetoram (allosteric agonist), thiacloprid, thiocyclam,thiosultap-sodium and AKD 1022.

M.6. GABA gated chloride channel antagonist compounds: chlordane,endosulfan, gamma-HCH (lindane); ethiprole, fipronil, pyrafluprole,pyriprole

M.7. Chloride channel activators: abamectin, emamectin benzoate,milbemectin, lepimectin;

M.8. METI I compounds: fenazaquin, fenpyroximate, pyrimidifen,pyridaben, tebufenpyrad, tolfenpyrad, flufenerim, rotenone;

M.9. METI II and III compounds: acequinocyl, fluacyprim, hydramethylnon;

M.10. Uncouplers of oxidative phosphorylation: chlorfenapyr, DNOC;

M.11. Inhibitors of oxidative phosphorylation: azocyclotin, cyhexatin,diafenthiuron, fenbutatin oxide, propargite, tetradifon;

M.12. Moulting disruptors: cyromazine, chromafenozide, halofenozide,methoxyfenozide, tebufenozide;

M.13. Synergists: piperonyl butoxide, tribufos;

M.14. Sodium channel blocker compounds: indoxacarb, metaflumizone;

M.15. Fumigants: methyl bromide, chloropicrin sulfuryl fluoride;

M.16. Selective feeding blockers: crylotie, pymetrozine, flonicamid;

M.17. Mite growth inhibitors: clofentezine, hexythiazox, etoxazole;

M.18. Chitin synthesis inhibitors: buprofezin, bistrifluron,chlorfluazuron, diflubenzuron, flucycloxuron, flufenoxuron,hexaflumuron, lufenuron, novaluron, noviflumuron, teflubenzuron,triflumuron;

M.19. Lipid biosynthesis inhibitors: spirodiclofen, spiromesifen,spirotetramat;

M.20. Octapaminergic agonsits: amitraz;

M.21. Ryanodine receptor modulators: flubendiamide and the phtalamidcompound (R)-,(S)-3-Chlor-N1-{2-methyl-4-[1,2,2,2-tetrafluor-1-(trifluormethyl)ethyl]phenyl}-N2-(1-methyl-2-methylsulfonylethyl)phthalamid (M21.1)

M.22. Isoxazoline compounds:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-pyridin-2-ylmethyl-benzamide(M22.1),4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2,2,2-trifluoro-ethyl)-benzamide(M22.2),4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(M22.3),4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M22.4)4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide(M22.5),4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide(M22.6),4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (M22.7) and5-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-[1,2,4]triazol-1-yl-benzonitrile(M22.8);M.23. Anthranilamide compounds: chloranthraniliprole, cyantraniliprole,

-   5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid    [4-cyano-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide    (M23.1),-   5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid    [2-chloro-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide    (M23.2),-   5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid    [2-bromo-4-cyano-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide(M23.3),-   5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid    [2-bromo-4-chloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide(M23.4),-   5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid    [2,4-dichloro-6-(1-cyclopropyl-ethylcarbamoyl)-phenyl]-amide    (M23.5),-   5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid    [4-chloro-2-(1-cyclopropyl-ethylcarbamoyl)-6-methyl-phenyl]-amide    (M23.6),-   N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-hydrazinecarboxylic    acid methyl ester (M23.7),-   N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N′-methyl-hydrazinecarboxylic    acid methyl ester (M23.8),-   N′-(2-{[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-5-chloro-3-methyl-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic    acid methyl ester (M23.9),-   N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-hydrazinecarboxylic    acid methyl ester (M23.10),-   N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N′-methyl-hydrazinecarboxylic    acid methyl ester (M23.11) and-   N′-(3,5-Dibromo-2-{[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carbonyl]-amino}-benzoyl)-N,N′-dimethyl-hydrazinecarboxylic    acid methyl ester (M23.12);    M.24. Malononitrile compounds:    2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,3-trifluoro-propyl)malononitrile    (CF₂H—CF₂—CF₂—CF₂—CH₂—C(CN)₂—CH₂—CH₂—CF₃) (M24.1) and    2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,3,4,4,4-pentafluorobutyl)-malonodinitrile    (CF₂H—CF₂—CF₂—CF₂—CH₂—C(CN)₂—CH₂—CH₂—CF₂—CF₃) (M24.2);    M.25. Microbial disruptors: Bacillus thuringiensis subsp.    Israelensi, Bacillus sphaericus, Bacillus thuringiensis subsp.    Aizawai, Bacillus thuringiensis subsp. Kurstaki, Bacillus    thuringiensis subsp. Tenebrionis;    M.26. Aminofuranone compounds:-   4-{[(6-Bromopyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on    (M26.1),-   4-{[(6-Fluoropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on    (M26.2),-   4-{[(2-Chlorol,3-thiazolo-5-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on    (M26.3),-   4-{[(6-Chloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on    (M26.4),-   4-{[(6-Chloropyrid-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-on    (M26.5),-   4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on    (M26.6),-   4-{[(5,6-Dichloropyrid-3-yl)methyl](2-fluoroethyl)amino}furan-2(5H)-on    (M26.7),-   4-{[(6-Chloro-5-fluoropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on    (M26.8),-   4-{[(6-Chloropyrid-3-yl)methyl](cyclopropyl)amino}furan-2(5H)-on    (M26.9) and-   4-{[(6-Chloropyrid-3-yl)methyl](methyl)amino}furan-2(5H)-on    (M26.10);    M.27. Various compounds: aluminium phosphide, amidoflumet,    benclothiaz, benzoximate, bifenazate, borax, bromopropylate,    cyanide, cyenopyrafen, cyflumetofen, chinomethionate, dicofol,    fluoroacetate, phosphine, pyridalyl, pyrifluquinazon, sulfur,    organic sulfur compounds, tartar emetic, sulfoxaflor,    N—R′-2,2-dihalo-1-R″cyclo-propanecarboxamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)hydrazone    or    N—R′-2,2-di(R″′)propionamide-2-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)-hydrazone,    wherein R′ is methyl or ethyl, halo is chloro or bromo, R″ is    hydrogen or methyl and R″′ is methyl or ethyl,    4-But-2-ynyloxy-6-(3,5-dimethyl-piperidin-1-yl)-2-fluoro-pyrimidine    (M27.1), Cyclopropaneacetic acid, 1,1′-[(3 S,4R,4aR,6S,6aS,12R,    12aS, 12bS)-4-[[(2-cyclopropylacetyl)oxy]methyl]-1,3,4,4a,5,6,6a,    12,12a, 12b-decahydro-12-hydroxy-4,6a,    12b-trimethyl-11-oxo-9-(3-pyridinyl)-2H,    11H-naphtho[2,1-b]pyrano[3,4-e]pyran-3,6-diyl]ester(M27.2) and    8-(2-Cyclopropylmethoxy-4-trifluoromethyl-phenoxy)-3-(6-trifluoromethyl-pyridazin-3-yl)-3-aza-bicyclo[3.2.1]octane(M27.3).    The commercially available compounds of the group M may be found in    The Pesticide Manual, 13th Edition, British Crop Protection    Council (2003) among other publications.

Paraoxon and their preparation have been described in Farm ChemicalsHandbook, Volume 88, Meister Publishing Company, 2001. Flupyrazofos hasbeen described in Pesticide Science 54, 1988, p. 237-243 and in U.S.Pat. No. 4,822,779. AKD 1022 and its preparation have been described inU.S. Pat. No. 6,300,348. The anthranilamides M23.1 to M23.6 have beendescribed in WO 2008/72743 and WO 200872783, those M23.7 to M23.12 inWO2007/043677. The phthalamide M 21.1 is known from WO 2007/101540.—Thealkynylether compound M27.1 is described e.g. in JP 2006131529. Organicsulfur compounds have been described in WO 2007060839. The isoxazolinecompounds M 22.1 to M 22.8 have been described in e.g. WO2005/085216, WO2007/079162, WO 2007/026965, WO 2009/126668 and WO2009/051956. Theaminofuranone compounds M 26.1 to M 26.10 have been described eg. in WO2007/115644. The pyripyropene derivative M 27.2 has been described in WO2008/66153 and WO 2008/108491. The pyridazin compound M 27.3 has beendescribed in JP 2008/115155. Malononitrile compounds as those (M24.1)and (M24.2) have been described in WO 02/089579, WO 02/090320, WO02/090321, WO 04/006677, WO 05/068423, WO 05/068432 and WO 05/063694.All of the documents referred to above are hereby incorporated byreference in their entirety.

Fungicides that may be mixed with the compounds of the inventioninclude, but are not limited to, acylalanines such as benalaxyl,metalaxyl, ofurace, oxadixyl; amine derivatives such as aldimorph,dodine, dodemorph, fenpropimorph, fenpropidin, guazatine, iminoctadine,spiroxamin, tridemorph; anilinopyrimidines such as pyrimethanil,mepanipyrim or cyrodinyl; antibiotics such as cycloheximid,griseofulvin, kasugamycin, natamycin, polyoxin or streptomycin; azolessuch as bitertanol, bromoconazole, cyproconazole, difenoconazole,dinicona-zole, epoxiconazole, fenbuconazole, fluquiconazole,flusilazole, hexaconazole, imazalil, metconazole, myclobutanil,penconazole, propiconazole, prochloraz, prothioconazole, tebuconazole,triadimefon, triadimenol, triflumizol, triticonazole, flutriafol;dicarboximides such as iprodion, myclozolin, procymidon, vinclozolin;dithiocarbamates such as ferbam, nabam, maneb, mancozeb, metam, metiram,propineb, polycarbamate, thiram, ziram, zineb; heterocyclic compoundssuch as anilazine, benomyl, boscalid, carbendazim, carboxin,oxycarboxin, cyazofamid, dazomet, dithianon, famoxadon, fenamidon,fenarimol, fuberidazole, flutolanil, furametpyr, isoprothiolane,mepronil, nuarimol, probenazole, proquinazid, pyrifenox, pyroquilon,quinoxyfen, silthiofam, thiabendazole, thifluzamid, thiophanate-methyl,tiadinil, tricyclazole, triforine; copper fungicides such as Bordeauxmixture, copper acetate, copper oxychloride, ba-sic copper sulfate;nitrophenyl derivatives such as binapacryl, dinocap, dinobuton,nitrophthalisopropyl; phenylpyrroles such as fenpiclonil or fludioxonil,Sulfur; other fungicides such as acibenzolar-S-methyl, benthiavalicarb,carpropamid, chlorothalonil, cyflufenamid, cymoxanil, diclomezin,diclocymet, diethofencarb, edifen-phos, ethaboxam, fenhexamid,fentin-acetate, fenoxanil, ferimzone, fluazinam, fosetyl,fosetyl-aluminum, iprovalicarb, hexachlorobenzene, metrafenon,pencycuron, propamocarb, phthalide, toloclofos-methyl, quintozene,zoxamid; strobilurins such as azoxystrobin, dimoxystrobin,fluoxastrobin, kresoxim-methyl, me-tominostrobin, orysastrobin,picoxystrobin or trifloxystrobin; sulfenic acid derivatives such ascaptafol, captan, dichlofluanid, folpet, tolylfluanid; cinnemamides andanalogs such as dimethomorph, flumetover or flumorph.

III. Uses and Methods

Due to their excellent activity, the compounds of formula (Id), and inparticular compounds of formula (Ie) and (S)-Ie, may be used forcontrolling pests. Accordingly, the present invention also provides amethod for controlling animal pests, which method comprises treating thepests, their food supply, their habitat or their breeding ground or acultivated plant, plant propagation materials (such as seed), soil,area, material or environment in which the pests are growing or maygrow, or the materials, cultivated plants, plant propagation materials(such as seed), soils, surfaces or spaces to be protected from pestattack or infestation with a pesticidally effective amount of a compoundof formula (Id), or a salt thereof, or a composition as defined above.

In one embodiment, the method of the invention serves for protectingplant propagation material (such as seed) and the plant which growstherefrom from animal pest attack or infestation and comprises treatingthe plant propagation material (such as seed) with a pesticidallyeffective amount of a compound of formula (Id) or an agriculturallyacceptable salt thereof as defined above or with a pesticidallyeffective amount of an agricultural composition as defined above andbelow. The method of the invention is not limited to the protection ofthe “substrate” (plant, plant propagation materials, soil material etc.)which has been treated according to the invention, but also has apreventive effect, thus, for example, according protection to a plantwhich grows from a treated plant propagation materials (such as seed),the plant itself not having been treated.

In one embodiment of the present invention related to agriculturalapplications, “animal pests” are preferably selected from arthropods andnematodes, more preferably from harmful insects, arachnids andnematodes, and even more preferably from insects, acarids and nematodes.

The invention further provides an agricultural composition for combatingsuch animal pests, which comprises such an amount of at least onecompound of formula (Id) or at least one agriculturally useful saltthereof, and at least one inert liquid and/or solid agriculturallyacceptable carrier that has a pesticidal action and, if desired, atleast one surfactant. Such a composition may contain a single activecompound of formula (Id), or a salt thereof, or a mixture of severalactive compounds of formula (Id), or their salts, according to thepresent invention. The composition according to the present inventionmay comprise an individual isomer or mixtures of isomers as well asindividual tautomers or mixtures of tautomers.

The animal pest, i.e. the insects, arachnids and nematodes, the plant,soil or water in which the plant is growing can be contacted with thepresent compounds of formula (Id) or composition(S) containing them byany application method known in the art. As such, “contacting” includesboth direct contact (applying the compounds/compositions directly on theanimal pest or plant—typically to the foliage, stem or roots of theplant) and indirect contact (applying the compounds/compositions to thelocus of the animal pest or plant).

The compounds of formula (Id) or the pesticidal compositions comprisingthem may be used to protect growing plants and crops from attack orinfestation by animal pests, especially insects, acaridae or arachnidsby contacting the plant/crop with a pesticidally effective amount ofcompounds of formula I. The term “crop” refers both to growing andharvested crops.

The compounds of the present invention and the compositions comprisingthem are particularly important in the control of a multitude of insectson various cultivated plants, such as cereal, root crops, oil crops,vegetables, spices, ornamentals, for example seed of durum and otherwheat, barley, oats, rye, maize (fodder maize and sugar maize/sweet andfield corn), soybeans, oil crops, crucifers, cotton, sunflowers,bananas, rice, oilseed rape, turnip rape, sugarbeet, fodder beet,eggplants, potatoes, grass, lawn, turf, fodder grass, tomatoes, leeks,pumpkin/squash, cabbage, iceberg lettuce, pepper, cucumbers, melons,Brassica species, melons, beans, peas, garlic, onions, carrots, tuberousplants such as potatoes, sugar cane, tobacco, grapes, petunias,geranium/pelargoniums, pansies and impatiens.

The compounds of the present invention are employed as such or in formof compositions by treating the insects or the plants, plant propagationmaterials, such as seeds, soil, surfaces, materials or rooms to beprotected from insecticidal attack with an insecticidally effectiveamount of the active compounds. The application can be carried out bothbefore and after the infection of the plants, plant propagationmaterials, such as seeds, soil, surfaces, materials or rooms by theinsects.

The present invention also includes a method of combating animal pestswhich comprises contacting the animal pests, their habitat, breedingground, food supply, cultivated plants, seed, soil, area, material orenvironment in which the animal pests are growing or may grow, or thematerials, plants, seeds, soils, surfaces or spaces to be protected fromanimal attack or infestation with a pesticidally effective amount of amixture of at least one active compound of formula (Id). Moreover,animal pests may be controlled by contacting the target pest, its foodsupply, habitat, breeding ground or its locus with a pesticidallyeffective amount of compounds of formula I. As such, the application maybe carried out before or after the infection of the locus, growingcrops, or harvested crops by the pest.

In one embodiment, the compounds of the invention can also be appliedpreventively to places at which occurrence of the pests is expected.

The compounds of formula (Id) may be also used to protect growing plantsfrom attack or infestation by pests by contacting the plant with apesticidally effective amount of compounds of formula (Id). As such,“contacting” includes both direct contact (applying thecompounds/compositions directly on the pest and/or plant—typically tothe foliage, stem or roots of the plant) and indirect contact (applyingthe compounds/compositions to the locus of the pest and/or plant).

“Locus” means a habitat, breeding ground, plant, seed, soil, area,material or environment in which a pest or parasite is growing or maygrow, excluding the body of an animal.

The term “plant propagation material” refers to any parts of a plantwhich are propagable. In general, a plant propagation material includesthe product of the ripened ovule of gymnosperm and angiosperm plantswhich occurs after fertilization and some growth within the mother plantand includes seed, fruits, spurious fruits, infructescences and alsorhizomes (rootstocks), corms, tubers, bulbs and scions.

The term “plant propagation material” is to be understood to denote allthe generative parts of the plant such as seeds and vegetative plantmaterial such as cuttings and tubers (e.g. potatoes), which can be usedfor the multiplication of the plant. This includes seeds, roots, fruits,tubers, bulbs, rhizomes, shoots, sprouts and other parts of plants.Seedlings and young plants, which are to be transplanted aftergermination or after emergence from soil, may also be included. Theseplant propagation materials may be treated prophylactically with a plantprotection compound either at or before planting or transplanting.

The term “cultivated plants” is to be understood as including plantswhich have been modified by breeding, mutagenesis or geneticengineering. Genetically modified plants are plants, which geneticmaterial has been so modified by the use of recombinant DNA techniquesthat under natural circumstances cannot readily be obtained by crossbreeding, mutations or natural recombination. Typically, one or moregenes have been integrated into the genetic material of a geneticallymodified plant in order to improve certain properties of the plant. Suchgenetic modifications also include but are not limited to targetedpost-transitional modification of protein(S) (oligo- or polypeptides)poly for example by glycosylation or polymer additions such asprenylated, acetylated or farnesylated moieties or PEG moieties(e.g. asdisclosed in Biotechnol Prog. 2001 July-August; 17(4):720-8., ProteinEng Des Sel. 2004 January; 17(1):57-66, Nat Protoc. 2007; 2(5):1225-35,Curr Opin Chem Biol. 2006 October; 10(5):487-91. Epub 2006 Aug. 28,Biomaterials. 2001 March; 22(5):405-17, Bioconjug Chem. 2005January-February; 16(1):113-21).

The term “cultivated plants” is to be understood also including plantsthat have been rendered tolerant to applications of specific classes ofherbicides, such as hydroxy-phenylpyruvate dioxygenase (HPPD)inhibitors; acetolactate synthase (ALS) inhibitors, such as sulfonylureas (see e.g. U.S. Pat. No. 6,222,100, WO 01/82685, WO 00/26390, WO97/41218, WO 98/02526, WO 98/02527, WO 04/106529, WO 05/20673, WO03/14357, WO 03/13225, WO 03/14356, WO 04/16073) or imidazolinones (seee.g. U.S. Pat. No. 6,222,100, WO 01/82685, WO 00/26390, WO 97/41218, WO98/02526, WO 98/02527, WO 04/106529, WO 05/20673, WO 03/14357, WO03/13225, WO 03/14356, WO 04/16073); enolpyruvylshikimate-3-phosphatesynthase (EPSPS) inhibitors, such as glyphosate (see e.g. WO 92/00377);glutamine synthetase (GS) inhibitors, such as glufosinate (see e.g.EP-A-0242236, EP-A-242246) or oxynil herbicides (see e.g. U.S. Pat. No.5,559,024) as a result of conventional methods of breeding or geneticengineering. Several cultivated plants have been rendered tolerant toherbicides by conventional methods of breeding (mutagenesis), forexample Clearfield® summer rape (Canola) being tolerant toimidazolinones, e.g. imazamox. Genetic engineering methods have beenused to render cultivated plants, such as soybean, cotton, corn, beetsand rape, tolerant to herbicides, such as glyphosate and glufosinate,some of which are commercially available under the trade namesRoundupReady® (glyphosate) and LibertyLink® (glufosinate).

The term “cultivated plants” is to be understood also including plantsthat are by the use of recombinant DNA techniques capable to synthesizeone or more insecticidal proteins, especially those known from thebacterial genus Bacillus, particularly from Bacillus thuringiensis, suchas ä-endotoxins, e.g. CryIA(b), CryIA(c), CryIF, CryIF(a2), CryIIA(b),CryIIIA, CryIIIB(b1) or Cry9c; vegetative insecticidal proteins (VIP),e.g. VIP1, VIP2, VIP3 or VIP3A; insecticidal proteins of bacteriacolonizing nematodes, for example Photorhabdus spp. or Xenorhabdus spp.;toxins produced by animals, such as scorpion toxins, arachnid toxins,wasp toxins, or other insect-specific neurotoxins; toxins produced byfungi, such Streptomycetes toxins, plant lectins, such as pea or barleylectins; agglutinins; proteinase inhibitors, such as trypsin inhibitors,serine protease inhibitors, patatin, cystatin or papain inhibitors;ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin,luffin, saporin or bryodin; steroid metabolism enzymes, such as3-hydroxysteroid oxidase, ecdysteroid-IDP-glycosyl-transferase,cholesterol oxidases, ecdysone inhibitors or HMG-CoA-reductase; ionchannel blockers, such as blockers of sodium or calcium channels;juvenile hormone esterase; diuretic hormone receptors (helicokininreceptors); stilben synthase, bibenzyl synthase, chitinases orglucanases. In the context of the present invention these insecticidalproteins or toxins are to be understood expressly also as pre-toxins,hybrid proteins, truncated or otherwise modified proteins. Hybridproteins are characterized by a new combination of protein domains,(see, for example WO 02/015701). Further examples of such toxins orgenetically-modified plants capable of synthesizing such toxins aredisclosed, for example, in EP-A 374 753, WO 93/007278, WO 95/34656, EP-A427 529, EP-A 451 878, WO 03/018810 und WO 03/052073. The methods forproducing such genetically modified plants are generally known to theperson skilled in the art and are described, for example, in thepublications mentioned above. These insecticidal proteins contained inthe genetically modified plants impart to the plants producing theseproteins protection from harmful pests from certain taxonomic groups ofarthropods, particularly to beetles (Coleoptera), flies (Diptera), andbutterflies and moths (Lepidoptera) and to plant parasitic nematodes(Nematoda).

The term “cultivated plants” is to be understood also including plantsthat are by the use of recombinant DNA techniques capable to synthesizeone or more proteins to increase the resistance or tolerance of thoseplants to bacterial, viral or fungal pathogens. Examples of suchproteins are the so-called “pathogenesis-related proteins” (PR proteins,see, for example EP-A 0 392 225), plant disease resistance genes (forexample potato cultivars, which express resistance genes acting againstPhytophthora infestans derived from the Mexican wild potato Solanumbulbocastanum) or T4-lysozym (e.g. potato cultivars capable ofsynthesizing these proteins with increased resistance against bacteriasuch as Erwinia amylvora). The methods for producing such geneticallymodified plants are generally known to the person skilled in the art andare described, for example, in the publications mentioned above.

The term “cultivated plants” is to be understood also including plantsthat are by the use of recombinant DNA techniques capable to synthesizeone or more proteins to increase the productivity (e.g. bio massproduction, grain yield, starch content, oil content or proteincontent), tolerance to drought, salinity or other growth-limitingenvironmental factors or tolerance to pests and fungal, bacterial orviral pathogens of those plants.

The term “cultivated plants” is to be understood also including plantsthat contain by the use of recombinant DNA techniques a modified amountof substances of content or new substances of content, specifically toimprove human or animal nutrition, for example oil crops that producehealth-promoting long-chain omega-3 fatty acids or unsaturated omega-9fatty acids (e.g. Nexera® rape).

The term “cultivated plants” is to be understood also including plantsthat contain by the use of recombinant DNA techniques a modified amountof substances of content or new substances of content, specifically toimprove raw material production, for example potatoes that produceincreased amounts of amylopectin (e.g. Amflora® potato).

In general, “pesticidally effective amount” means the amount of activeingredient needed to achieve an observable effect on growth, includingthe effects of necrosis, death, retardation, prevention, and removal,destruction, or otherwise diminishing the occurrence and activity of thetarget organism. The pesticidally effective amount can vary for thevarious compounds/compositions used in the invention. A pesticidallyeffective amount of the compositions will also vary according to theprevailing conditions such as desired pesticidal effect and duration,weather, target species, locus, mode of application, and the like.

In the case of soil treatment or of application to the pests dwellingplace or nest, the quantity of active ingredient ranges from about0.0001 to about 500 g per 100 m², preferably from about 0.001 to about20 g per 100 m².

Customary application rates in the protection of materials are, forexample, from about 0.01 g to about 1000 g of active compound per m²treated material, desirably from about 0.1 g to about 50 g per m².

Insecticidal compositions for use in the impregnation of materialstypically contain from about 0.001 to about 95 weight %, preferably fromabout 0.1 to about 45 weight %, and more preferably from about 1 toabout 25 weight % of at least one repellent and/or insecticide.

For use in treating crop plants, the rate of application of the activeingredients of this invention may be in the range of about 0.1 g toabout 4000 g per hectare, desirably from about 25 g to about 600 g perhectare, more desirably from about 50 g to about 500 g per hectare.

The compounds of formula (Id) are effective through both contact (viasoil, glass, wall, bed net, carpet, plant parts or animal parts), andingestion (bait, or plant part).

The compounds of the invention may also be applied against non-cropinsect pests, such as ants, termites, wasps, flies, mosquitos, crickets,or cockroaches. For use against said non-crop pests, compounds offormula (Id) are preferably used in a bait composition. The bait can bea liquid, a solid or a semisolid preparation (e.g. a gel). Solid baitscan be formed into various shapes and forms suitable to the respectiveapplication e.g. granules, blocks, sticks, disks. Liquid baits can befilled into various devices to ensure proper application, e.g. opencontainers, spray devices, droplet sources, or evaporation sources. Gelscan be based on aqueous or oily matrices and can be formulated toparticular necessities in terms of stickiness, moisture retention oraging characteristics.

The bait employed in the composition is a product, which is sufficientlyattractive to incite insects such as ants, termites, wasps, flies,mosquitos, crickets etc. or cockroaches to eat it.

The attractiveness can be manipulated by using feeding stimulants or sexpheromones. Food stimulants are chosen, for example, but notexclusively, from animal and/or plant proteins (meat-, fish- or bloodmeal, insect parts, egg yolk), from fats and oils of animal and/or plantorigin, or mono-, oligo- or polyorganosaccharides, especially fromsucrose, lactose, fructose, dextrose, glucose, starch, pectin or evenmolasses or honey. Fresh or decaying parts of fruits, crops, plants,animals, insects or specific parts thereof can also serve as a feedingstimulant. Sex pheromones are known to be more insect specific. Specificpheromones are described in the literature and are known to thoseskilled in the art.

For use in bait compositions, the typical content of active ingredientis from about 0.001 weight % to about 15 weight %, desirably from about0.001 weight % to about 5% weight % of active compound.

Formulations of compounds of formula (Id) as aerosols (e.g. in spraycans), oil sprays or pump sprays are highly suitable for thenon-professional user for controlling pests such as flies, fleas, ticks,mosquitos or cockroaches. Aerosol recipes are preferably composed of theactive compound, solvents such as lower alcohols (e.g. methanol,ethanol, propanol, butanol), ketones (e.g. acetone, methyl ethylketone), paraffin hydrocarbons (e.g. kerosenes) having boiling ranges ofapproximately 50 to 250° C., dimethylformamide, N-methylpyrrolidone,dimethyl sulfoxide, aromatic hydrocarbons such as toluene, xylene,water, furthermore auxiliaries such as emulsifiers such as sorbitolmonooleate, oleyl ethoxylate having 3-7 mol of ethylene oxide (e.g.Labrafil® M 1944 CS), fatty alcohol ethoxylate, perfume oils such asethereal oils, esters of medium fatty acids with lower alcohols,aromatic carbonyl compounds, if appropriate stabilizers such as sodiumbenzoate, amphoteric surfactants, lower epoxides, triethyl orthoformateand, if required, propellants such as propane, butane, nitrogen,compressed air, dimethyl ether, carbon dioxide, nitrous oxide, ormixtures of these gases.

The oil spray compositions differ from the aerosol recipes in that nopropellants are used. For use in spray compositions, the content ofactive ingredient is from about 0.001 to about 80 weights %, preferablyfrom about 0.01 to about 50 weight % and most preferably from about 0.01to about 15 weight %.

The compounds of formula (Id), or salts thereof, and their respectivecompositions can also be used in mosquito and fumigating coils, smokecartridges, vaporizer plates or long-term vaporizers and also in mothpapers, moth pads or other heat-independent vaporizer systems.

Methods to control infectious diseases transmitted by insects (e.g.malaria, dengue and yellow fever, lymphatic filiariasis, andleishmaniasis) with compounds of formula (Id), or salts thereof, and itsrespective compositions also comprise treating surfaces of huts andhouses, air spraying and impregnation of curtains, tents, clothingitems, bed nets, tsetse-fly trap or the like. Insecticidal compositionsfor application to fibers, fabric, knitgoods, non-wovens, nettingmaterial or foils and tarpaulins preferably comprise a mixture includingthe insecticide, optionally a repellent and at least one binder.Suitable repellents for example are N,N-Diethyl-meta-toluamide (DEET),N,N-diethylphenylacetamide (DEPA),1-(3-cyclohexan-1-yl-carbonyl)-2-methylpiperine,(2-hydroxymethylcyclohexyl) acetic acid lactone, 2-ethyl-1,3-hexandiol,indalone, Methylneodecanamide (MNDA), a pyrethroid not used for insectcontrol such as((+/−)-3-allyl-2-methyl-4-oxocyclopent-2-(+)-enyl-(+)-trans-chrysantemate(Esbiothrin), a repellent derived from or identical with plant extractslike limonene, eugenol, (+)-Eucamalol (1), (−)-1-epi-eucamalol or crudeplant extracts from plants like Eucalyptus maculata, Vitex rotundifolia,Cymbopogan martinii, Cymbopogan citratus (lemon grass), Cymopogannartdus (citronella). Suitable binders are selected for example frompolymers and copolymers of vinyl esters of aliphatic acids (such as suchas vinyl acetate and vinyl versatate), acrylic and methacrylic esters ofalcohols, such as butyl acrylate, 2-ethylhexylacrylate, and methylacrylate, mono- and di-ethylenically unsaturated hydrocarbons, such asstyrene, and aliphatic dienes, such as butadiene. The impregnation ofcurtains and bednets is done in general by dipping the textile materialinto emulsions or dispersions of the insecticide or spraying them ontothe nets.

The compounds of formula (Id) and their compositions can also be usedfor protecting wooden materials such as trees, board fences, sleepers,etc. and buildings such as houses, outhouses, factories, but alsoconstruction materials, furniture, leathers, fibers, vinyl articles,electric wires and cables etc. from ants and/or termites, and forcontrolling ants and termites from doing harm to crops or human being(e.g. when the pests invade into houses and public facilities). Thecompounds of formula (Id) are applied not only to the surrounding soilsurface or into the under-floor soil in order to protect woodenmaterials but can also be applied to lumbered articles such as surfacesof the under-floor concrete, alcove posts, beams, plywoods, furniture,etc., wooden articles such as particle boards, half boards, etc. andvinyl articles such as coated electric wires, vinyl sheets, heatinsulating material such as styrene foams, etc. In case of applicationagainst ants doing harm to crops or human beings, the ant controller ofthe present invention is applied to the crops or the surrounding soil,or is directly applied to the nest of ants or the like.

IV. Seed Treatment

In some embodiments of the invention, the compounds of formula (Id) arealso suitable for the treatment of seeds in order to protect the seedfrom insect pest, in particular from soil-living insect pests and theresulting plant's roots and shoots against soil pests and foliarinsects.

The compounds of formula (Id) are particularly useful for the protectionof the seed from soil pests and the resulting plant's roots and shootsagainst soil pests and foliar insects. The protection of the resultingplant's roots and shoots is preferred. More preferred is the protectionof resulting plant's shoots from piercing and sucking insects, whereinthe protection from aphids is most preferred.

The present invention therefore comprises a method for the protection ofseeds from insects, in particular from soil insects and of theseedlings' roots and shoots from insects, in particular from soil andfoliar insects, said method comprising contacting the seeds beforesowing and/or after pregermination with a compound of the generalformula (Id), or a salt thereof. Particularly preferred is a method,wherein the plant's roots and shoots are protected, more preferably amethod, wherein the plants shoots are protected from piercing andsucking insects, most preferably a method, wherein the plants shoots areprotected from aphids.

The term seed embraces seeds and plant propagules of all kinds includingbut not limited to true seeds, seed pieces, suckers, corms, bulbs,fruit, tubers, grains, cuttings, cut shoots and the like and means in apreferred embodiment true seeds.

The term seed treatment comprises all suitable seed treatment techniquesknown in the art, such as seed dressing, seed coating, seed dusting,seed soaking and seed pelleting. The present invention also comprisesseeds coated with or containing the active compound.

The term “coated with and/or containing” generally signifies that theactive ingredient is for the most part on the surface of the propagationproduct at the time of application, although a greater or lesser part ofthe ingredient may penetrate into the propagation product, depending onthe method of application. When the said propagation product is(re)planted, it may absorb the active ingredient.

Suitable seed includes, but is not limited to, seed of cereals, rootcrops, oil crops, vegetables, spices, ornamentals, for example seed ofdurum and other wheat, barley, oats, rye, maize (fodder maize and sugarmaize/sweet and field corn), soybeans, oil crops, crucifers, cotton,sunflowers, bananas, rice, oilseed rape, turnip rape, sugarbeet, fodderbeet, eggplants, potatoes, grass, lawn, turf, fodder grass, tomatoes,leeks, pumpkin/squash, cabbage, iceberg lettuce, pepper, cucumbers,melons, Brassica species, melons, beans, peas, garlic, onions, carrots,tuberous plants such as potatoes, sugar cane, tobacco, grapes, petunias,geranium/pelargoniums, pansies and impatiens.

In addition, the active compounds may also be used for the treatmentseeds from plants, which tolerate the action of herbicides or fungicidesor insecticides owing to breeding, including genetic engineeringmethods. For example, the active compounds can be employed in treatmentof seeds from plants, which are resistant to herbicides from the groupconsisting of the sulfonylureas, imidazolinones, glufosinate-ammonium orglyphosate-isopropylammonium and analogous active substances (see forexample, EP-A-0242236, EP-A-242246) (WO 92/00377) (EP-A-0257993, U.S.Pat. No. 5,013,659) or in transgenic crop plants, for example cotton,with the capability of producing Bacillus thuringiensis toxins (Bttoxins) which make the plants resistant to certain pests (EP-A-0142924,EP-A-0193259).

Furthermore, the active compounds of the invention can be used also forthe treatment of seeds from plants, which have modified characteristicsin comparison with existing plants consist, which can be generated forexample by traditional breeding methods and/or the generation ofmutants, or by recombinant procedures). For example, a number of caseshave been described of recombinant modifications of crop plants for thepurpose of modifying the starch synthesized in the plants (e.g. WO92/11376, WO 92/14827, WO 91/19806) or of transgenic crop plants havinga modified fatty acid composition (WO 91/13972).

The seed treatment application of the active compound is typicallycarried out by spraying or by dusting the seeds before sowing of theplants and before emergence of the plants.

Compositions which are especially useful for seed treatment include:

A Soluble concentrates (SL, LS)

D Emulsions (EW, EO, ES)

E Suspensions (SC, OD, FS)

F Water-dispersible granules and water-soluble granules (WG, SG)

G Water-dispersible powders and water-soluble powders (WP, SP, WS)

H Gel-Formulations (GF)

I Dustable powders (DP, DS)

Conventional seed treatment compositions include, for example, flowableconcentrates FS, solutions LS, powders for dry treatment DS, waterdispersible powders for slurry treatment WS, water-soluble powders SSand emulsion ES and EC and gel composition GF. These compositions can beapplied to the seed diluted or undiluted. Application to the seeds iscarried out before sowing, either directly on the seeds or after havingpregerminated the latter.

In a preferred embodiment a FS composition is used for seed treatment.Typically, a FS composition may comprise about 1-800 g/l of activeingredient, about 1-200 g/l Surfactant, about 0 to 200 g/l antifreezingagent, about 0 to 400 g/l of binder, about 0 to 200 g/l of a pigment andup to about 1 liter of a solvent, preferably water.

Especially preferred FS compositions of compounds of formula I for seedtreatment usually comprise from about 0.1 to about 80% by weight (1 to800 g/l) of the active ingredient, from about 0.1 to about 20% by weight(1 to 200 g/l) of at least one surfactant, e.g. about 0.05 to about 5%by weight of a wetter and from about 0.5 to about 15% by weight of adispersing agent, up to about 20% by weight, e.g. from about 5 to about20% of an anti-freeze agent, from about 0 to about 15% by weight, e.g.about 1 to about 15% by weight of a pigment and/or a dye, from about 0to about 40% by weight, e.g. about 1 to about 40% by weight of a binder(sticker/adhesion agent), optionally up to about 5% by weight, e.g. fromabout 0.1 to about 5% by weight of a thickener, optionally from about0.1 to about 2% of an anti-foam agent, and optionally a preservativesuch as a biocide, antioxidant or the like, e.g. in an amount from about0.01 to about 1% by weight and a filler/vehicle up to 100% by weight.

Seed Treatment compositions may additionally also comprise binders andoptionally colorants. Binders can be added to improve the adhesion ofthe active materials on the seeds after treatment. Suitable bindersinclude, but are not limited to, homo- and copolymers from alkyleneoxides like ethylene oxide or propylene oxide, polyvinylacetate,polyvinylalcohols, polyvinylpyrrolidones, and copolymers thereof,ethylene-vinyl acetate copolymers, acrylic homo- and copolymers,polyethyleneamines, polyethylene amides and polyethyleneimines,polysaccharides like celluloses, tylose and starch, polyolefin homo- andcopolymers like olefin/maleic anhydride copolymers, polyurethanes,polyesters, polystyrene homo and copolymers

Optionally, colorants or dyes may also be included in the composition.Suitable colorants or dyes for seed treatment compositions include, butare not limited to, Rhodamin B, C.I. Pigment Red 112, C.I. Solvent Red1, pigment blue 15:4, pigment blue 15:3, pigment blue 15:2, pigment blue15:1, pigment blue 80, pigment yellow 1, pigment yellow 13, pigment red112, pigment red 48:2, pigment red 48:1, pigment red 57:1, pigment red53:1, pigment orange 43, pigment orange 34, pigment orange 5, pigmentgreen 36, pigment green 7, pigment white 6, pigment brown 25, basicviolet 10, basic violet 49, acid red 51, acid red 52, acid red 14, acidblue 9, acid yellow 23, basic red 10, basic red 108.

A gelling agent may also be used in some compositions of the invention.One non-limiting example of a gelling agent is carrageen (Satiagel®)

In the treatment of seed, the application rates of the compounds offormula (Id) are generally from about 0.1 g to about 10 kg per 100 kg ofseed, preferably from about 1 g to about 5 kg per 100 kg of seed, morepreferably from about 1 g to about 1000 g per 100 kg of seed and inparticular from about 1 g to about 200 g per 100 kg of seed.

The invention therefore also relates to seed comprising a compound offormula (Id), or an agriculturally useful salt thereof, as definedherein. The amount of the compound of formula (Id), or theagriculturally useful salt thereof, will in general vary from about 0.1g to about 10 kg per 100 kg of seed, preferably from about 1 g to about5 kg per 100 kg of seed, in particular from about 1 g to about 1000 gper 100 kg of seed. The application rate will vary depending on thespecific crop, as known to those in skill in the art. For specific cropssuch as lettuce the rate may be higher than specified above.

The invention will now be further described by way of the followingnon-limiting examples.

EXAMPLES

The invention is further described by the following non-limitingexamples which further illustrate the invention, and are not intended,nor should they be interpreted to, limit the scope of the invention.

Synthesis Examples Synthesis Example 1: Synthesis of (S)-Ie

The compound of formula (S)-Ie of the invention was prepared accordingto Scheme 2 below. Compound 2-1 is described in U.S. Pat. No. 7,951,828B1, incorporated herein by reference. Preparation of the compound 2-4 isdescribed in U.S. Pat. No. 8,217,180 B2 and U.S. Pat. No. 8,546,618 B2,both incorporated herein by reference in their entirety. Cinchonaalkaloid-based chiral phase transfer catalyst similar to 2-6 areprepared according to the procedures described in, for example, U.S.Pat. No. 9,126,995 B2, WO 2011/104089 and US 2014/0206633, allincorporated herein by reference. Further, Matoba et al., Angew. Chem.2010, 122, 5898-5902 describes the use of these catalysts to prepareenantiomerically pure isoxazoline compounds.

Step 1

1-Chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene (2-1, 100 g, 0.31mol) and tetrahydrofuran (THF, 200 ml, 2 volumes) were charged into a500 ml reactor under an atmosphere of nitrogen. The mixture was cooledto −15 to −20° C. and a solution of i-PrMgCl in THF (2M, 170 ml, 0.34mol, 1.1 eq.) was added to the reactor slowly (over 30 min.) at −20 to−5° C. The resulting mixture was stirred for an additional 0.5-1 hourand checked for reaction completion by GCMS, which showed that thestarting material was consumed. Methyl 2,2,2-trifluoroacetate was addedto the reaction mixture over 0.5-1 hour at −20 to −5° C. The resultingmixture was stirred overnight at −20 to −10° C. and checked for reactionconversion. When the reaction was complete, aqueous HCl (1 M, 500 ml)was added and the mixture was stirred for 1-2 hours at −5 to 5° C. Thequenched reaction mixture was extracted with cyclohexane twice (500 ml,200 ml) and the combined organic layers were concentrated under vacuumto provide intermediate 2-3 as a crude product (62.0 g, purity 98.4%,77.7%).

Step 2

2-methyltetrahydrofuran (2-Me-THF, 25 ml, 5 vol.), intermediate 2-4 (5.0g, 17 mmol, 1 eq.), molecular sieves (1.0 g, 20% w/w) and potassiumcarbonate (0.7 g, 5.1 mmol, 0.3 eq.) were charged into a 100 ml, 3-neckflask. The resulting mixture was warmed to 75-85° C. and compound 2-3was added drop-wise to the mixture at 75-85° C. over 0.5-1 hour. Themixture was then stirred for an additional 4 hours at the sametemperature and tested by HPLC for reaction progression. AdditionalK₂CO₃ (0.2 g, 1.7 mmol) and 2-3 (0.1 g, 0.34 mmol, 0.2 eq.) were addedand the mixture was stirred for a further 16 hours. The mixture wascooled to 30-40° C. and filtered. The filtrate was concentrated to abrown solid. The product was purified by chromatography (silica gel,petroleum ether/ethyl acetate) to yield the product as a yellow solid(6.6 grams, 79.7% purity). The product was then recrystallized fromacetonitrile to yield compound 2-5 in 44.9% yield (4.0 grams) and 91.6%purity.

Step 3

Dichloromethane (DCM, 150 ml, 30 vol.) and 2-5 (5.0 g, 7.95 mmol, 1.0eq.) were charged into a 500 ml 3-neck flask. The mixture was stirredfor 10-30 min. until the compound was dissolved and then cooled to −10to 15° C. The chiral phase transfer catalyst 2-6 was added (0.18 g,0.024 mmol, 0.03 eq.) to the solution and then a solution of NH₂OH (50%w/w)/NaOH/H₂O (20 ml, 5 vol.) was added dropwise at −10 to 15° C. over0.5-1 hour. The resulting mixture was stirred for 16 hours at −10 to 15°C. and sampled for analysis by HPLC to check the reaction completion, atwhich time there was less than 3.0% of the starting material. Theorganic layer was separated and washed with a saturated solution ofKH₂PO₄ (20 ml, 4 vol.) twice. The resulting organic layer was furtherwashed with brine (20 ml) twice and then concentrated under vacuum at30-40° C. with the concomitant addition of toluene (20 ml, 4 vol.) andthen concentrated to dryness.

To 4.9 grams of the isolated crude product was charged 15 ml of toluenein a 3-neck flask and the mixture was heated to 60-70° C. to dissolvethe solid. The resulting solution was cooled slowly to 45-500 over 1hour and seed (0.025 g, 0.05% w/w) was added. The seeded mixture wasstirred for 1 hour at 45-50° C. and then cooled further to 37-42° C.over 1 hour and then stirred for a further 6 hours. During this time theproduct was observed to crystallize from solution. The mixture wascooled to 30-35° C. over 1 hour and stirred for 3 hours. The solid wasfiltered and the cake washed with toluene (10 ml, 2 vol.). The cake wasthen dried in an oven at 40-450 under vacuum for 6 hours to yield 2.3grams (45.1% yield) of (S)-Ie in 99.4% purity and 99.3% chiral purity.

Using the same approach but an alternative chiral phase transfercatalyst (e.g. isomer of 2-6), the compound (R)-Ie may be made.Alternatively, a racemic compound of formula (Ie) may be preparedwithout the use of a chiral phase transfer catalyst. The final step inthese processes are described in the examples below.

Synthesis Example 2: Racemic Compound (Ie)

Step 3

Into a 5 liter reactor was charged 2 liters (10 volumes) of DCM and200.0 grams (0.32 mol, 1.0 eq.) and the mixture was stirred for 10-30minutes to dissolve the solid. The solution was cooled to 0-5° C. andNH₂OH (50% w/w)/NaOH/H₂O (104.9 g/76.3 g/1.0 L) was added dropwise at0-25° C. over 30-60 min. The resulting mixture was stirred at 10-25° C.for 3 hours and then sampled to check the reaction conversion by HPLC,which showed that the starting material was present at less than 3.5%.The mixture was allowed to settle and the DCM layer was washed with asaturated solution of KH₂PO₄ (0.8 L, 4 vol.) twice. The resultingorganic layer was further washed with brine (0.8 L, 4 vol.) twice. Thecombined organic layers were concentrated under vacuum at 30-40° C. todryness and to provide the crude product as a yellow solid (196.0 g,purity: 94%, chiral purity: 49.7%). The crude product was purified bychromatography over silica gel using DCM:ethanol (100:1 to 20:1) to get138.0 grams of the pure product (purity: 99.5%, chiral purity: 49.7%).The product was further dried to remove toluene to yield 125.0 grams asa light yellow solid (yield, 61.2%, purity: 99.5%, chiral purity:49.7%).

Synthesis Example 3: Preparation of Compound (S)-If

The compound of formula (S)-If was prepared using a process very similarto that shown above for (S)-Ie with the key difference that1-iodo-3,5-dichlorobenzene was used as starting material instead of1-Chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene. The process for thepreparation of (S)-If is shown in Scheme 3 below and the detailedprocedure for Step 3 is provided.

Step 3

Dichloromethane (150 ml, 30 vol.) and intermediate 3-5 (5.0 g, 8.66mmol, 1.0 eq.) were charged into a 3-neck 500 ml flask and stirred for10-30 minutes to dissolve the solid. The solution was then cooled to0-5° C. and chiral phase transfer catalyst 2-6 was added (0.20 g, 0.026mmol, 0.03 eq.). To the resulting solution was added a solution of NH₂OH(50% w/w)/NaOH/H₂O (20 ml, 5 vol.) drop-wise at 0 to 5° C. over 0.5-1hour. The resulting reaction mixture was stirred for 2 hours at 0-5° C.and then sampled to check the reaction completion by HPLC, which showedless than 1% starting material. The layers were allowed to settle andthe DCM layer was washed with saturated KH₂PO₄ (20 ml, 4 vol.) twice.The organic layer was then washed with brine (20 ml, 4 vol.) twice. Thecombined organic layers were concentrated under vacuum at 30-40° C. withconcomitant addition of toluene (20 ml, 4 vol., twice) and thenconcentrated to dryness. Toluene (15 ml, 3 vol.) and the crude product(5.0 g) were charged into a 50 ml, 3-neck flask and the mixture washeated to 60-70° C. to dissolve the solid. The resulting mixture wascooled slowly to 45-50° C. over 2 hours and filtered. The filter cakewas washed with toluene (10 ml, 2 vol.) and the filtrate was dried in anoven under vacuum at 40-50° C. for 6 hours to yield the product (2.5 g,yield: 49.0%, purity 99.4%, chiral purity: 99.3%).

Synthesis Example 4: Preparation of Compound (Ic) where X¹ and X²═Cl andX³═F

The compound of formula (Ic), where where X¹ and X²═Cl and X³═F, wasprepared according to a process very similar to that shown in Schemes 2and 3 above with the key difference that1,3-dichloro-2-fluoro-5-iodobenzene was used as starting materialinstead of 1-chloro-2-fluoro-5-iodo-3-(trifluoromethyl)benzene. Step 3of the process is described in detail below.

Compound 4-5 (5, 8.4 mmol, 1.0 eq.) and THF (30 ml, 6 vol.) were chargedinto a 100 ml 3-neck flask. The solid was dissolved and NaOH (1.5 g,50%, 18.5 mmol, 2.2 eq.) and hydroxylamine sulfate (0.6 g, 4.62 mmol,0.55 eq.) were added to the mixture at 0-5° C. The reaction mixture wasstirred for 90 minutes and sampled for analysis by HPLC, which indicatedthat less than 1.0% of the starting material was left. To the resultingmixture was added KH₂PO₄ (1.3 g, 10.9 mmol, 1.3 eq.) and the mixture waswarmed to 20-25° C. The layers were allowed to separate and the organiclayer isolated. The THF was removed by distillation with concomitantaddition of acetonitrile (20 ml, 4 vol.) twice and then concentrated todryness. Acetonitrile (20 ml, 4 vol.) was added to dissolve the residueand the solution was cooled to 25-30° C. slowly and stirred at thistemperature for 180 min. The solid was filtered and the cake washed withacetonitrile (10 ml, 2 vol.). The solid was dried under vacuum at 30-35°C. for 6 hours to obtain the product (2.1 g, 98.9% purity, yield,41.2%).

Veterinary Long-Acting Injectable Formulation Examples

The following long-acting injectable compositions are prepared by mixingthe following ingredients:

Formulation Example 5

Compound of formula (Ia) 30% (w/v) Ethanol  9% (w/v) PEG 400 QS.

Formulation Example 6

Compound of formula (Ia) 15% (w/w) PEG 400 85% (w/w)

Formulation Example 7

Compound of formula (Ia) 26% (w/w) PEG 400 74% (w/w)

Formulation Example 8

Compound of formula (Ia) 26% (w/w) PEG 400 66% (w/w) Ethanol  8% (w/w)

Formulation Example 9

Compound of formula (Ia) 26% (w/w) PEG 400 66% (w/w) Isopropanol  8%(w/w)

Formulation Example 10

Compound of formula (Ia) 26% (w/w) PEG 400 64% (w/w) Capryol 90 10%(w/w)

Formulation Example 11

Compound of formula (Ia) 26% (w/w) PEG 66% (w/w) Benzyl alcohol  8%(w/w)

Formulation Example 12

Compound of formula (S)-Ia 13% (w/w) PEG 400 79% (w/w) Ethanol  8% (w/w)

Formulation Example 13

Compound of formula Ic where X¹, X³ = Cl, X² is F 30% (w/v) Ethanol  9%(w/v) PEG 400 QS.

Formulation Example 14

Compound of formula (Ic), where X¹ = Cl, X² = F, X³ = CF₃ 30% (w/v)Ethanol  9% (w/v) PEG 400 QS.

Formulation Example 15

Compound of formula(S)-Ic, where X¹, X³ = Cl, X² is F 13% (w/w) PEG 40079% (w/w) Ethanol   8% (w/w).

Formulation Example 16

Compound of formula(S)-Ic, where X¹ = Cl, X² = F, X³ = 13% (w/w) CF₃ PEG400 79% (w/w) Ethanol   8% (w/w).

Formulation Example 17

Compound of formula (S)-Ic, where X¹, X³ = Cl, X² is H 13% (w/w) PEG 40079% (w/w) Ethanol  8% (w/w).

Formulation Example 18

Compound of formula (S)-Ic, where X¹, X², X³ = chloro 13% (w/w) PEG 40079% (w/w) Ethanol  8% (w/w).

Formulation Example 19

Compound of formula (S)-Ic, X¹ = Cl, X² = F, X³ = CF₃ 10% (w/v) Ethanol 8% (w/w) PEG 400 QS.

Formulation Example 20

Compound of formula (S)-Ic, X¹ = Cl, X² = F, X³ = CF₃ 10% (w/v) PEG 400QS.

Formulation Example 21

Compound of formula (S)-Ic, X¹ = Cl, X² = F, X³ = CF₃ 5% (w/v) PEG 400QS.

Formulation Example 22

Compound of formula (S)-Ic, X¹ = Cl, X² = F, X³ = CF₃ 10% (w/v) Ethanol 3% (w/v) PEG 400 QS.

Formulation Example 23

Compound of formula (S)-Ic, X¹ = Cl, X² = F, X³ = CF₃ 5% (w/v) Ethanol8% (w/v) PEG 400 QS.

Formulation Example 24

Compound of formula (S)-Ic, X¹ = Cl, X² = F, X³ = CF₃ 2.5% (w/v) PEG 400QS.

Formulation Example 25

Compound of formula (S)-Ic, X¹ = Cl, X² = F, X³ = CF₃ 2.5% (w/v) Ethanol  8% (w/v) PEG 400 QS.

Formulation Example 26

Compound of formula (S)-Ie  20% (w/v) Medium chain triglycerides (e.g.Miglyol ® 812) QS Sorbitan monooleate 0.5% (w/v) Benzyl alcohol   8%(w/v).

Formulation Example 27

Compound of formula (S)-Ie  10% (w/v) Medium chain triglycerides (e.g.Miglyol ® 812) QS Sorbitan monooleate 0.5% (w/v) Benzyl alcohol   8%(w/v).

Formulation Example 28

Compound of formula (S)-Ie   5% (w/v) Medium chain triglycerides (e.g.Miglyol ® 812) QS Sorbitan monooleate 0.5% (w/v) Benzyl alcohol   8%(w/v).

Formulation Example 29

Compound of formula (S)-Ie 2.5% (w/v) Medium chain triglycerides (e.g.Miglyol ® 812) QS Sorbitan monooleate 0.5% (w/v) Benzyl alcohol   8%(w/v).

Formulation Example 30

Compound of formula (S)-Ie  20% (w/v) PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812)  30% (w/v) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol   8% (w/v).

Formulation Example 31

Compound of formula (S)-Ie  10% (w/v) PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812)  30% (w/v) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol   8% (w/v).

Formulation Example 32

Compound of formula (S)-Ie   5% (w/v) PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812)  30% (w/v) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol   8% (w/v).

Formulation Example 33

Compound of formula (S)-Ie 2.5% (w/v) PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812)  30% (w/v) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol   8% (w/v).

Formulation Example 34

Compound of formula (S)-Ie  20% (w/v) Propylene glycoldicaprylate/dicaprate QS (e.g. Miglyol ® 840) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol   8% (w/v).

Formulation Example 35

Compound of formula (S)-Ie  10% (w/v) Propylene glycoldicaprylate/dicaprate QS (e.g. Miglyol ® 840) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol   8% (w/v).

Formulation Example 36

Compound of formula (S)-Ie   5% (w/v) Propylene glycoldicaprylate/dicaprate QS (e.g. Miglyol ® 840) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol   8% (w/v).

Formulation Example 37

Compound of formula (S)-Ie 2.5% (w/v) Propylene glycoldicaprylate/dicaprate QS (e.g. Miglyol ® 840) Sorbitan monooleate 0.5%(w/v) Benzyl alcohol  8% (w/v).

Formulation Example 38

Compound of formula (S)-Ie 20% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate 30% (w/v) (e.g. Miglyol ® 840) Sorbitan monooleate0.  Benzyl alcohol   8% (w/v).

Formulation Example 39

Compound of formula (S)-Ie 10% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate 30% (w/v) (e.g. Miglyol ® 840) Sorbitan monooleate0.5% (w/v)  Benzyl alcohol  8% (w/v).

Formulation Example 40

Compound of formula (S)-Ie 5% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate 30% (w/v)  (e.g. Miglyol ® 840) Sorbitanmonooleate 0.5% (w/v)   Benzyl alcohol  8% (w/v).

Formulation Example 41

Compound of formula (S)-Ie 2.5% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate  30% (w/v) (e.g. Miglyol ® 840) Sorbitanmonooleate 0.5% (w/v) Benzyl alcohol  8% (w/v).

Formulation Example 42

Compound of formula (S)-Ie 20% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate 30% (w/v) (e.g. Miglyol ® 840) Sorbitan monooleate0.5% (w/v).

Formulation Example 43

Compound of formula (S)-Ie 10% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate 30% (w/v) (e.g. Miglyol ® 840) Sorbitan monooleate0.5% (w/v).

Formulation Example 44

Compound of formula (S)-Ie  5% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate 30% (w/v) (e.g. Miglyol ® 840) Sorbitan monooleate0.5% (w/v).

Formulation Example 45

Compound of formula (S)-Ie 2.5% (w/v) PEG 400 QS Propylene glycoldicaprylate/dicaprate  30% (w/v) (e.g. Miglyol ® 840) Sorbitanmonooleate  0.5% (w/v).

Formulation Example 46

Compound of formula (S)-Ie 20% (w/v) PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812) 30% (w/v) Sorbitan monooleate 0.5%(w/v).

Formulation Example 47

Compound of formula (S)-Ie 10% (w/v) PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812) 30% (w/v) Sorbitan monooleate 0.5%(w/v).

Formulation Example 48

Compound of formula (S)-Ie  5% (w/v) PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812) 30% (w/v) Sorbitan monooleate 0.5%(w/v).

Formulation Example 49

Compound of formula (S)-Ie 2.5% (w/v)  PEG 400 QS Medium chaintriglycerides (e.g. Miglyol ® 812) 30% (w/v) Sorbitan monooleate 0.5%(w/v).

Example 50: Viscosity of Long-Acting Formulations

The viscosity of the formulations in Examples 19-25 was measured todetermine their suitability for injection. Polyethylene glycol 400 (PEG400) was used as a reference. The conditions below were used for themeasurement:

Instrument: LVDV-E Brookfield viscometer

Spindle: S31

Speed: 60 revolutions per minute (rpm)

Temperature: 25° C.

Sample volume: 9.0 mL

Measurement time: 2 to 3 minutes

Measured viscosity Calculated Total Formulation in cPs Allowable ErrorExample 19 75.5 ±5.75 Example 20 134.5 ±6.344 Example 21 109.5 ±6.093Example 22 102.5 ±6.023 Example 23 60.0 ±5.598 Example 24 95.5 ±5.953Example 25 55.5 ±5.553 PEG 400 93.0 ±5.929The viscosity of each of the compositions from Examples 18 to 24 wasfound to be suitable for administration by injection.

Efficacy Examples Example 51: Efficacy of Injectable Formulation AgainstRhipicephalus (Boophilus) microplus Ticks

The efficacy of long-acting injectable compositions of the inventioncomprising the compounds of formula (Ie) and (S)-Ie, againstRhipicephalus microplus ticks on cattle was determined against anuntreated control group. The efficacy of compositions comprising thecompounds (Ie) and (S)-e were also compared with injectable compositionscomprising afoxolaner (formula Ia,4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide),and comparative compounds of formulae (If) and (S)-If shown below.

Each compound was formulated in an injectable composition at aconcentration of 10% (w/v) in a carrier comprising 8% (w/v) ethanol andQ.S. with polyethylene glycol 400. The racemic compounds afoxolaner and(If) were dosed at 1.0 mg/kg body weight and the (S)-enantiomers ((S)-Ieand (S)-If) were dosed at 0.5 mg/kg body weight. Six healthy head ofcattle were used in each study group. Cattle in Group 1 were untreated(control). Cattle in Groups 2, 3, 4, 5 and 6 were treated on Day 0subcutaneously with injectable compositions comprising the compounds offormula Ie, (S)-If, (S)-Ie, afoxolaner (Ia) and (If), respectively.Several weeks before treatment, cattle were infested three times a weekwith approximately 2500 Rhipicephalus microplus larvae to establishongoing infestations. Each animal was challenged by infestation withapproximately 5000 R. microplus larvae on Days 7 and 21 and every 14days thereafter. Ticks dropping from each animal in the previous 24hours were collected daily and counted from Day 1 until the end of thestudy. The cattle in study Groups 3, 5 and 6 were not infested furtherwhen the efficacy of the treatment dropped significantly.

Tables 1A, 1B and 1C below show the total tick count % efficacy ofinjectable compositions comprising compounds of the invention ((Ie) and(S)-Ie) against R. microplus for selected days through Day 110 posttreatment compared with the untreated control group and the comparisonisoxazoline compounds. As evidenced from the data in Tables 1A, 1B and1C below, the compositions comprising the compounds (Ie) and (S)-Ie ofthe invention dosed at 1.0 mg/kg and 0.5 mg/kg, respectively, providesurprising and unexpected efficacy against Rhipicephalus microplus ticksfor an extended period of time compared with compositions comprisingafoxolaner, (If) or (S)-If. Further, the efficacy of compounds (Ie) and(S)-Ie is also faster-acting than compositions comprising the otherisoxazoline compounds. The superior efficacy of compounds (Ie) (racemic)and (S)-Ie against R. microplus ticks is unexpected and unpredictable.

TABLE 1A Tick Count Efficacy Against Rhipicephalus microplus Average %Efficacy (Tick Count) Treatment Day Day Day Day Day Day Day Group 5 1020 30 40 49 55 Group 2 (Ie) 69 100 100 100 100 100 100 Group 3((S)-If)39 27 33 86 100 36 0 Group 4 ((S)-Ie) 66 93 100 100 100 100 100 Group 5afoxolaner 38 48 77 99 100 94 73 Group 6 (If) 70 62 57 84 100 70 14

TABLE 1B Tick Count Efficacy Against Rhipicephalus microplus Average %Efficacy (Tick Count) Treatment Day Day Day Day Day Day Day Group 60 6570 75 80 85 88 Group 2 (Ie) 100 100 100 100 100 100 100 Group 3 ((S)-If)— — — — — — — Group 4 ((S)-Ie) 100 100 100 100 100 90 88 Group 5afoxolaner 71 48 3 0 — — — Group 6 (If) — — — — — — —

TABLE 1C Tick Count Efficacy against Rhipicephalus microplus Average %Efficacy (Tick Count) Day Day Day Day Treatment Group 95 100 105 110Group 2 (Ie) 100 100 93 82 Group 3 ((S)-If) — — — — Group 4 ((S)-Ie)  92 88 76 65 Group 5 afoxolaner — — — — Group 6 (If) — — — —

Example 52: Efficacy of Long-Acting Injectable Compositions AgainstHaematobia irritans (Horn Fly) on Cattle

The efficacy of a long-acting injectable composition comprising thecompound of formula (S)-Ie against horn fly on cattle was evaluated. Twogroups of 15 cattle were selected for the study and randomly assigned toone of two groups. The cattle in Group 1 were untreated and the cattlein Group 2 were treated with a long-acting composition of the inventioncontaining 10% (w/v) of the compound of formula (S)-Ie in a carriercomprising 8% (w/v) ethanol in PEG 400 (QS). The composition wasadministered to the cattle in Group 2 at a dose of 0.25 mL/50 kg bodyweight. Each animal was naturally infested with horn flies, and horn flycounts were performed on Days −2, 3, 7, 10, 13, 16, 20, 23, 27, 30, 34,37, 43, 45 and 48. Tables 2A and 2B below provide the horn fly countsand the % reduction of the treated group relative to the control

TABLE 2A Arithmetic Mean of Horn Fly Counts & % Reduction Treatment DayDay Day Day Day Day Day Day Group 3 7 10 13 16 20 23 27 Group 1 254.3136.0 78.3 60.0 104.7 83.0 53.3 59.3 (untreated) Group 2 26.7 35.0 16.022.0 44.7 36.0 30.7 22.7 ((S)-Ie) % Reduction 89.5 74.3 79.6 63.3 57.356.6 42.5 61.8

TABLE 2B Arithmetic Mean of Horn Fly Counts & % Reduction Treatment DayDay Day Day Day Day Group 30 34 37 43 45 48 Group 1 71.0 47.7 73.3 43.066.7 44.0 (untreated) Group 2 23.0 26.3 28.0 26.0 43.0 30.3 ((S)-Ie) %Reduction 67.6 44.8 61.8 39.5 35.5 31.1

Having thus described in detail various embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

What is claimed is:
 1. A long-acting injectable composition for thetreatment of an ectoparasitic infection or infestation in an animal,said composition comprising a) an effective amount of a parasiticidalisoxazoline active agent, which is a compound of formula (Ie):

or a pharmaceutically acceptable salt thereof; b) a pharmaceuticallyacceptable polymer which is a liquid PEG and, c) optionally, aco-solvent wherein said co-solvent is a polar solvent miscible in water,wherein no other pharmaceutically acceptable polymers are present, andwherein the composition treats the ectoparasitic infection orinfestation for about 3 to 6 months.
 2. The long-acting injectablecomposition according to claim 1, wherein the parasiticidal isoxazolineactive agent is enriched in an enantiomer.
 3. The long-acting injectablecomposition according to claim 2, wherein the enantiomer is a compoundof formula (S)-Ie:

or a pharmaceutically acceptable salt thereof.
 4. The long-actinginjectable composition according to any one of claims 1 and 2-3, whereinthe liquid PEG is PEG 200, PEG 300 or PEG 400, or a mixture thereof. 5.The long-acting injectable composition according to any one of claims 1and 2-3, wherein the composition further comprises a co-solvent, andwherein the co-solvent is ethanol or isopropanol, or a mixture thereof.6. The long-acting injectable composition according to claim 1, whereinthe composition further comprises a pharmaceutically acceptableexcipient, and wherein the excipient is a surfactant.
 7. The long-actinginjectable composition according to claim 6, wherein the surfactant isselected from the group consisting of glyceryl monooleate, sorbitanmonooleate, sodium lauryl sulfate, poloxamers, propylene glycolmonolaurate, glycerol caprylate/caprate, and a combination thereof. 8.The long-acting injectable composition according to claim 1, wherein thecomposition comprises: a) about 5 to 15% (w/v) of the parasiticidalisoxazoline compound of formula (Ie):

or a pharmaceutically acceptable salt thereof; b) a pharmaceuticallyacceptable polymer which is a liquid PEG; c) optionally, about 5% to 40%(w/v) of co-solvent, wherein said co-solvent is selected from ethanoland isopropanol; d) optionally, about 0.01% to about 2.0% (w/v) of anantioxidant; and e) optionally, about 0.01% to about 5.0% (w/v) of apharmaceutically acceptable additive, excipient or mixtures thereofwherein the only pharmaceutically acceptable polymer present in saidlong-acting injectable composition is a liquid PEG and wherein theliquid PEG is present in the overall composition in a proportionrepresenting the complement to 100% of the composition.
 9. Thelong-acting injectable composition according to any one of claims 1,2-3, and 8, wherein said composition provides an efficacy of at least90% against ticks for about 3 to 4 months.
 10. The long-actingcomposition according to any one of claims 1, 2, 3, and 8, which furthercomprises an effective amount of at least one additional active agent.11. The long-acting composition according to claim 10, wherein the atleast one additional pharmaceutically active agent is a macrocycliclactone, a neonicotinoid active agent, a 1-N-arylpyrazole active agent,a cyclic depsipeptide, a benzimidazole, an imidazothiazole, atetrahydropyrimidine active agent, an organophosphate active agent,levamisole, a paraherquamide active agent, a marcfortine active agent,praziquantel, closantel, pyrantel, morantel, clorsulon, a spinosynactive agent, a spinosoid active agent, an amino acetonitrile activeagent, an aryloazol-2-yl cyanoethyl active agent or an insect growthregulator.
 12. The long-acting composition according to claim 11,wherein the macrocyclic lactone is abamectin, dimadectin, doramectin,emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin,ML-1,694,554, milbemectin, milbemycin D, moxidectin or nemadectin.
 13. Amethod for treating ectoparasites in an animal in need thereof for aperiod of 3 to 6 months which comprises administering the long-actinginjectable composition according to any one of claims 1 and 8 to saidanimal.
 14. The method according to claim 13 wherein the animal is adog, a cat, an ovine or a bovine.
 15. The method according to claim 13wherein the parasites are treated for about 5 to 6 months.
 16. Themethod according to claim 13 wherein the ectoparasites are fleas and/orticks.
 17. The composition according to claim 1, wherein the about 3 to6 month treatment period is associated with a dose of the compositionthat is about 0.5 mg to about 2.5 mg of the isoxazoline active agent perkg of body weight of said animal.
 18. The composition according to claim3, wherein the about 3 to 6 month treatment period is associated with adose of the composition that is about 0.5 mg to about 2.5 mg of theisoxazoline active agent per kg of body weight of said animal.
 19. Thecomposition according to claim 8, wherein the about 3 to 6 monthtreatment period is associated with a dose of the composition that isabout 0.5 mg to about 2.5 mg of the isoxazoline active agent per kg ofbody weight of said animal.